KR20080104063A - Novel crystal of substituted phenylalkanoic acid and production process - Google Patents

Abstract

[PROBLEMS] To provide 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid, methyl 3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl] propionate, or methyl 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate in a more preferred form for use as a medicine; and an improved method therefor. [MEANS FOR SOLVING PROBLEMS] Provided are crystals of a compound which is 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid, methyl 3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]-propionate, or methyl 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl] propionate. Also provided is a process for producing the crystals.

Description

New determination and preparation of substituted phenylalkanoic acid {NOVEL CRYSTAL OF SUBSTITUTED PHENYLALKANOIC ACID AND PRODUCTION PROCESS}

The present invention relates to novel crystals. More specifically, 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, 3- [4- (indane) -2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate, or 3- [3-amino-4- (indan-2-yloxy) It relates to a novel crystal of a compound of any of -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate, or a method for producing a crystal.

3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid has a prostaglandin production inhibitory effect and a leukotriene production inhibitory effect It is reported that these are useful for the prevention and / or treatment of various inflammatory diseases, autoimmune diseases, allergic diseases or pain due to lipid mediators, and methods for preparing these compounds.

Patent Document 1: WO 03/70686

Disclosure of the Invention

Problem to be solved of the invention

In using this compound as a medicine, it is providing the more preferable form and improved method.

Means for Solving the Invention

3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid of Compound 1 (hereinafter referred to as "Compound Compound 1" May be referred to), according to the known production method described above, 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) A 2% aqueous sodium hydroxide solution was added to a methanol solution of phenyl] propionate, stirred at 60 ° C for 16 hours, the reaction mixture was concentrated under reduced pressure, acidified with 5% hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. In this known production method, the compound is obtained as a colorless to brown oily substance. MEANS TO SOLVE THE PROBLEM In the case of administering this compound 1 as a medicine, the present inventors considered that the new improvement which makes handling more simple is needed, examined variously, confirmed that this compound 1 is crystallized, and came to complete this invention.

According to this invention, since the crystal of this compound 1 is provided, handling becomes easy in a formulation process, and it is very preferable that it is easy to make the content of this compound uniform for every preparation. In addition, from the viewpoint of removal of solvents and the like, the crystals of the compound can be easily and completely removed from solvents, and are suitable for industrial scale production.

Further, the present inventors have conducted studies on the crystals, and as a result, found that Compound 1 contains novel A-type and B-type crystals having the properties described below, and each of them has desirable properties. A method of selectively acquiring has been established to complete the present invention.

Moreover, according to the well-known manufacturing method mentioned above, 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate ( Hereinafter, "this compound 2" may be called) ethanol of 3- (3-bromo-4-hydroxy-5-nitrophenyl) methyl propionate and 1-methyl-1H-indazol-5-boric acid 2M aqueous sodium carbonate solution, toluene and tetrakistriphenylphosphinepalladium (0) were added to the solution, which was stirred for 16 hours at 80 ° C. After washing with brine in order to dry the organic layer, the solvent was distilled off under reduced pressure, and the residue was further purified by flash column chromatography. This known production method does not mention the form of the compound at all. In this well-known manufacturing method, handling is not necessarily easy at the time of manufacture. Moreover, this inventor confirmed that even when using this compound as a medicine, there exist problems in making content uniform, the ease of removal of a solvent, etc., and the like. Furthermore, it confirmed that the compound 2 can be acquired as a new crystal | crystallization, and came to complete this invention.

Moreover, according to the above-mentioned well-known manufacturing method, 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl- 1H-indazol-5-yl) phenyl] methyl propionate ( Hereinafter, "this compound 3" may be called, and "this compound 1", "this compound 2", and "this compound 3" may be called "this compound", and the above-mentioned compound 2 Raney 2800 nickel was added to the ethyl acetate / methanol mixed solution, the mixture was stirred at room temperature under hydrogen atmosphere for 6 hours, and then the reaction mixture was filtered, the solvent of the filtrate was distilled off under reduced pressure, and the residue was then purified by column chromatography. Get In this well-known manufacturing method, although the form of this compound 3 is not mentioned at all, handling is not necessarily easy at the time of manufacture. In addition, the inventors of the present invention confirmed that even when the compound 3 is used as a medicament, there is a problem in making the content uniform, removing the solvent, and the like. It confirmed that it could acquire newly as a crystal | crystallization, and came to complete this invention.

That is, this invention is as follows.

(1) 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, 3- [4- (indane-2 -Yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate, or 3- [3-amino-4- (indan-2-yloxy) -5 Crystals of a compound of any one of-(1-methyl-1H-indazol-5-yl) phenyl] methyl propionate.

(2) Crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid.

(3) Crystals of 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate.

(4) Crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate.

(5) The crystal consists of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, powder X-ray (1) characterized in that in the diffraction spectrum, 2θ is Form A crystal having at least one characteristic peak at at least 6.9 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 °, 25.0 ± 0.2 ° or 27.5 ± 0.2 ° Or the crystal described in (2).

In addition, the 2θ angle in the powder X-ray diffraction spectrum may cause some measurement errors that can be tolerated by various factors, and the measured value is usually ± 0.3 °, typically ± 0.2 °, and ± in a more preferable measurement. It fluctuates by about 0.1 °. Thus, in the present specification, it should be understood that the 2θ angle based on the measured value for a particular sample may include such an acceptable error.

(5-1) Crystals consist of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, powder Characterized in that in the X-ray diffraction spectrum, 2θ is Form A crystal with peaks characteristic at 6.9 ± 0.2 °, 14.4 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 02 °, 25.0 ± 0.2 ° and 27.5 ± 0.2 ° The crystal according to the above (1), (2) or (5).

(6) The crystal consists of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, with differential scanning calories The crystal according to the above (1), (2), (5) or (5-1), which is an A crystal having an endothermic peak of about 182 ° C in the analysis (heating rate of 10 ° C / min).

In addition, the endothermic peak in the differential scanning calorimetry is inherent in the physical properties of the crystal of the compound, but in actual measurement, in addition to the measurement error, in some cases, the cause of incorporation of an acceptable amount of impurities, etc. The possibility of fluctuations in the melting point can not be denied. Therefore, those skilled in the art can fully understand how much the actual endothermic peak temperature measured in the present invention can fluctuate and, if exemplarily, ± 5 ° C., typically ± 3 ° C., if desired, ± An error of about 2 ° C. may be assumed.

(7) The crystal consists of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, and an infrared absorption spectrum (1), (2), (5), and (5-), wherein the crystals are Form A crystals having a remarkable infrared absorption band in the vicinity of the wavenumbers 3361, 2938, 1712, 1204, 1011, and 746 cm ^-1 . The crystal according to any one of 1) or (6).

Periodically, some measurement errors are permissible in the infrared absorption spectral wave number, and it is thought that the present invention can also include this error. The person skilled in the art can fully understand the degree of the error, and for example, referring to the European Pharmacopeia 4th Edition, within ± 0.5% of the wavenumber scale in comparison with the reference spectrum in the confirmation test by the infrared absorption spectrum. The degree of correspondence is indicated. Although it does not specifically limit in this invention, It should just refer to such an error which can be considered normally, For example, as one measure, about ± 0.8% with respect to the actual value of a wave number scale, Preferably it is about ± 0.5%, Especially preferably, Can illustrate a change of ± 0.2%.

(7-1) 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl as described in any one of said (5)-(7) whose crystal purity is at least 90 weight% or more. Form A crystals of -1H-indazol-5-yl) phenyl] propionic acid.

In addition, although it becomes (5)-(7) in the said text, it is the meaning including the invention of a lower number according to the order arrange | positioned, Specifically, it is (5), (5-1), (6), (7) ). The same applies to the following.

(8) The crystal consists of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and is powder X-ray (1) or (2) above, wherein 2θ in the diffraction spectrum is a Form B crystal having at least one characteristic peak at at least 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° or 22.9 ± 0.2 ° Described crystals.

(8-1) Crystals consist of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, powder (1), wherein in the X-ray diffraction spectrum, 2θ is a type B crystal having peaks characteristic of 14.4 ± 0.2 °, 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° and 22.9 ± 0.2 ° The crystal described in (2) or (8).

(9) The crystal consists of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, with differential scanning calories The crystal according to the above (1), (2), (8) or (8-1), which is a B-type crystal having an endothermic peak of about 203 ° C in the analysis (heating rate of 10 ° C / min).

(10) The crystal consists of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, and an infrared absorption spectrum (1), (2), (8), and (8-1), wherein the crystals are B-type crystals having a remarkable infrared absorption band near the wavenumbers 2939, 1720, 1224, 1016 and 751 cm ⁻¹ . Or the crystal according to any one of (9).

(10-1) 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl as described in any one of said (8)-(10) whose crystal purity is at least 90 weight% or more. Form B crystals of -1H-indazol-5-yl) phenyl] propionic acid.

(10-2) The crystal consists of 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate, 2θ in the powder X-ray diffraction spectrum is a crystal having at least one characteristic peak at at least 7.6 ° ± 0.2 °, 15.3 ° ± 0.2 °, 18.0 ° ± 0.2 °, 21.3 ° ± 0.2 ° and 26.9 ° ± 0.2 ° Crystal according to the above (1) or (3).

(10-3) The crystal consists of 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate, (1), (2) characterized in that 2θ in the powder X-ray diffraction spectrum has peaks characteristic at 7.6 ± 0.2 °, 15.3 ± 0.2 °, 18.0 ± 0.2 °, 21.3 ± 0.2 ° and 26.9 ± 0.2 ° 3) or the crystal described in (10-2).

(10-4) The crystal consists of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate, Wherein in the powder X-ray diffraction spectrum 2θ is a crystal having at least one characteristic peak at at least 8.6 ± 0.2 °, 12.7 ± 0.2 °, 17.2 ± 0.2 °, 17.6 ± 0.2 °, 18.9 ± 0.2 ° and 21.0 ± 0.2 ° Crystal according to the above (1) or (4).

(10-5) The crystal consists of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate, Wherein in the powder X-ray diffraction spectrum, 2θ is a crystal having peaks characteristic at 8.6 ± 0.2 °, 12.7 ± 0.2 °, 17.2 ± 0.2 °, 17.6 ± 0.2 °, 18.9 ± 0.2 ° and 21.0 ± 0.2 ° The crystal described in (1), (4) or (10-4).

(11) 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5- in any one of (1) to (10-5) above Mono) phenyl] propionic acid crystals, or Form A crystals or Form B crystals, or 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5 -Crystals of nitrophenyl] methyl propionate, or 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate A pharmaceutical composition comprising any one of them as an active ingredient and a pharmaceutically acceptable carrier.

(12) The pharmaceutical composition according to the above (11), wherein the pharmaceutically acceptable carrier is a dried substance and the pharmaceutical composition is a dry formulation.

(13) 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) according to any one of (5) to (7) above. A pharmaceutical composition comprising a form A crystal having a crystal purity of at least 90% by weight or more as the active ingredient of a form A crystal of phenyl] propionic acid and a pharmaceutically acceptable carrier.

(14) 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) according to any one of (8) to (10) above. A pharmaceutical composition comprising a form B crystal having a crystal purity of at least 90% by weight or more as the active ingredient of a form B crystal of phenyl] propionic acid and a pharmaceutically acceptable carrier.

(15) Add acid to a solution under basic conditions of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid Thus, a crystal composed of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid is produced to obtain a crystal. 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazole- according to any one of the above (5) to (7-1) A process for preparing Form A crystals of 5-yl) phenyl] propionic acid.

(16) A solution under basic conditions of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid is 3- (3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] alkaline hydrolyzate of lower alkyl ester of propionic acid A process for producing Form A crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid as described in 15).

(16-1) Alkali hydrolysis of lower alkyl esters of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid After the reaction, the reaction solution consists of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid. Crystal | crystallization is produced | generated and crystal | crystallization is obtained, 3- [3-amino- 4- (indan-2-yloxy) -5- (1 in any one of said (5)-(7-1) characterized by the above-mentioned. A method for producing Form A crystals of -methyl-1H-indazol-5-yl) phenyl] propionic acid.

(17) 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, acetone, dichloromethane, methanol, acetic acid 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl from a solution dissolved in any one or two or more solvents selected from the group consisting of ethyl, methanol / acetic acid mixtures and acetonitrile Crystallization of -1H-indazol-5-yl) phenyl] propionic acid, 3- [3-amino-4- (indan-2-yljade) according to any one of (8) to (10-1) above. C) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid A process for producing Form B crystals.

(18) Add acid to a solution under basic conditions of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid Immediately before the formation of a crystal consisting of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid, Form B crystal of a compound is acquired by adding Form B crystal | crystallization as a seed crystal, The manufacturing method of the crystal | crystallization in any one of said (8)-(10-1) characterized by the above-mentioned.

(18-1) A solution under basic conditions of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid, It is an alkaline hydrolyzate of lower alkyl ester of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid Method for producing Form B crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to the above (18) .

(18-2) Alkali hydrolysis of lower alkyl esters of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid After the reaction, an acid was added to the reaction solution, which was composed of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid. The crystal according to any one of (8) to (10-1) above, wherein the Form B crystal of the compound is obtained by adding the Form B crystal of the compound to the reaction solution immediately before the crystal is formed. Method of preparation.

(19) 3- [4- (indane-2-yloxy) -3 dissolved in any one or two or more solvents selected from the group consisting of toluene, ethyl acetate, tetrahydrofuran, acetone, dimethoxyethane, methanol Any one selected from the group consisting of heptane, diisopropyl ether, isopropanol, t-butylmethyl ether, and water in a solution of-(1-methyl-1H-indazol-5-yl) -5-nitrophenyl] propionate, or 3- [4- (Indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] characterized by the addition of two or more solvents to form a crystal. Method for producing a crystal of methyl propionate.

(19-1) The crystal has characteristic peaks, typically at least one of 7.6 ± 0.2 °, 15.3 ± 0.2 °, 18.0 ± 0.2 °, 21.3 ± 0.2 ° and 26.9 ± 0.2 ° in the powder X-ray diffraction spectrum, typically Is a crystal having all these peaks, the production method according to the above (19).

(20) 3- [3-amino-4- (indan-2-yloxy) -5- () dissolved in any one or two or more solvents selected from the group consisting of toluene, ethyl acetate, tetrahydrofuran and acetone. To a solution of methyl 1-methyl-1H-indazol-5-yl) phenyl] propionate, a crystal is formed by adding one or two or more solvents selected from the group consisting of heptane, isopropanol, methanol, and water. A process for preparing the crystal of [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate.

(20-1) The crystal features at least one of 8.6 ± 0.2 °, 12.7 ± 0.2 °, 17.2 ± 0.2 °, 17.6 ± 0.2 °, 18.9 ± 0.2 °, and 21.0 ± 0.2 ° in the powder X-ray diffraction spectrum. The production method according to the above (20), which is a crystal having a specific peak, typically all these peaks.

The crystal of Compound 1 is advantageous in that it has a great advantage in the formulation process, such as that it is easy to make the content of the Compound of each formulation uniform, and the crystal is easier to remove solvents and the like than in the case of an oily substance. It is also suitable for manufacturing on an industrial scale.

As a crystal of this compound 1 used by the specific form of this invention, a type A crystal is mentioned as a preferable example. Form A crystals of Compound 1 are defined by any one or a combination of two or more of the various properties of the above-described inventions (5) to (7-1), or various properties identified by the examples, test examples, and the like of the present specification. It is a decision. In addition to the advantages of the above-described crystals of Compound 1, these A-type crystals exhibit certain properties, and thus exhibit desirable properties as preparations or in medicinal effects as compared to simple uncontrolled crystals, and in manufacturing processes. I confirmed that it was. The so-called A-type crystals are preferable, for example, in view of higher solubility in an aqueous solvent as compared with the B-type crystals described later.

In order to maximize the desirable effect of the A crystal, it is preferable to use an A crystal which is substantially an A crystal. As such an A crystal, the crystal purity (percentage) of the A crystal is usually 90 weight% or more is mentioned, 95 weight% or more is a preferable example, 97 weight% or more is more preferable, 99 weight% or more is more preferable, and about 100 weight% is illustrated as an especially preferable example. do. Moreover, in some cases, 93 weight% or more is preferable, 98 weight% or more is more preferable, 99.5 weight% or more is especially preferable. Moreover, in using as a medicine of this invention, 80 weight% or more may be sufficient normally. Moreover, as a preferable form of A-type crystal | crystallization, the crystal which does not contain substantially crystalline forms other than A-type is also illustrated. "Substantially free" means that crystalline forms other than Form A crystals are preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 3% by weight or less, particularly preferably 1% by weight or less, Most preferably, it does not contain at all.

Moreover, a B-type crystal | crystallization is mentioned as a preferable example as a crystal used by further another aspect of this invention. Form B crystals of Compound 1 are crystals defined by any one or a combination of two or more of the various properties of the above-described inventions (8) to (10-1), or various properties identified in Examples, test examples, and the like of the present specification. to be. In addition to the advantages of the above-described crystals of Compound 1, the B-type crystals exhibit certain properties, and thus exhibit desirable properties as preparations or medicinal agents as compared to simple uncontrolled crystals. To indicate. In addition, the B-type crystals have higher filterability than the A-type crystals, and the flow characteristics are further improved separately from this, and when producing B-type crystals in large quantities, for example, a filtration step and / or a dehydration step It is expected that the time required for the back can be shortened. In addition, Form B crystals are more preferable when producing dry preparations and solid preparations. It was also confirmed that the water content of B-type crystals after filtration dehydration was lower than that of Form A crystals after filtration dehydration. Particularly, in the case of mass production, it is expected that shortening of drying time and reduction of thermal energy are expected. In addition, apart from this, it is considered that this B-type crystal has substantially better morphological stability than the A-type crystal. In order to maximize the desirable effect of the B crystals, it is preferable to use a B crystal which is substantially a B crystal. As the B crystal, the purity of the B crystal is usually 90% by weight. At least 95% by weight may be mentioned, and preferred examples are at least 95% by weight, more preferably at least 97% by weight, still more preferably at least 99% by weight, and about 100% by weight. Moreover, in some cases, 93 weight% or more is preferable, 98 weight% or more is more preferable, 99.5 weight% or more is especially preferable. Moreover, in using as a medicine of this invention, 80 weight% or more may be sufficient normally. Moreover, as a preferable form of form B crystal | crystallization, the crystal which does not contain substantially crystalline forms other than form B is also illustrated. "Substantially free" means that crystalline forms other than Form B crystals are preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 3% by weight or less, particularly preferably 1% by weight or less, Most preferably, it does not contain at all.

In addition, as a crystal purity (percentage) of Form A crystals, the present weight of the crystals of Form A crystals may be divided by the present weight of Compound 1 to 100 times. Here, as a measuring method of the present weight of the crystal | crystallization of a form A crystal and the present weight of this compound 1, you may apply any of the following methods, and also the measuring method which added the appropriate change to these can be used.

In addition, although a measurement error may appear more than necessary depending on a measuring method, it is also preferable to confirm and correct the magnitude of an error using a known quantity standard product. For example, in this invention, the measurement value of the crystal computed by the measuring method by differential scanning calorimetry (especially the specific measuring conditions described in this specification can be mentioned as a particularly preferable example) is measured by HPLC (especially in this specification It is especially preferable that the crystal purity is displayed as a value calculated by dividing by the measured value of Compound 1, calculated by the specific measurement conditions described in the above), and calculated by 100 times. Moreover, the crystal purity (percentage) of Form B crystals is also the same as the above description, and the measurement method can be changed as appropriate, but the measurement method by differential scanning calorimetry (particularly, specific measurement conditions described in the present specification) may be mentioned as particularly preferred examples. The purity of the crystal as calculated by dividing the measured value of the crystal obtained by) by 100 times divided by the measured value of the compound 1 calculated by the HPLC (in particular, the specific measurement conditions described in the present specification) is particularly preferable. It is particularly preferable to be displayed.

That is, the amount of each crystal present can be calculated by differential scanning calorimetry or by measuring the intensity of characteristic peaks in powder X-ray diffraction spectrum, infrared absorption spectrum, solid ¹³ C-NMR spectrum, Raman spectrum, and the like. In particular, in measuring the abundance of Form A crystals and Form B crystals of Compound 1 as described above, a method of measuring by differential scanning calorimetry is preferable. The present invention is specifically explained by taking the form A crystal of Compound 1 as an example. In differential scanning calorimetry (for example, a suitable temperature increase rate may be, for example, 50 ° C./min) at a proper temperature increase rate, the crystal is pure as a crystal. Using a form A crystal as a standard, plotting the calibration curve by plotting the weight of the standard (mg) and the area (mJ) of the endothermic peak near about 185 ° C based on the melting of the form A crystal, and in the sample to be measured. The abundance of Form A crystals can be calculated by comparing the area (mJ) of the endothermic peak near about 185 ° C with the calibration curve. Moreover, the amount of abundance can be computed similarly to the Form B crystal of this compound 1. That is, the endothermic peak of the differential scanning calorimetry of the B-type crystal | crystallization is normally used, for example, using pure B-type crystal | crystallization as a standard product, and what is necessary is just to measure the endothermic peak of about 205 degreeC.

In measurement methods other than differential scanning calorimetry, that is, measurement methods such as powder X-ray diffraction spectra, infrared absorption spectra, solid ¹³ C-NMR spectra, and Raman spectra, calibration curves are prepared using standard products in the same manner as differential scanning calorimetry. By making it, the amount of a existent crystal form of interest can be calculated.

In particular, in the case of calculating the abundance of the target crystal form by a measurement method other than differential scanning calorimetry, that is, a measurement method such as powder X-ray diffraction spectrum, infrared absorption spectrum, solid ¹³ C-NMR spectrum, or Raman spectrum, By appropriately selecting peaks characteristic of the crystalline form of, a calibration curve can be created to calculate the amount of abundant crystals of interest.

Moreover, as an optical system used for powder X-ray diffraction spectrum measurement, a general concentrated optical system or a parallel beam optical system is illustrated. Although it does not specifically limit as an optical system to be used, When measuring resolution and intensity | strength, it is preferable to measure using a intensive optical system. Moreover, when it is going to suppress the orientation which is a phenomenon which becomes a fixed direction by the shape of a crystal (needle shape, plate shape, etc.), it is preferable to measure using a parallel beam optical system. As a measuring apparatus of a intensive optical system, XRD-6000 (made by Shimadzu Corporation.), MultiFlex (made by Rigaku Corporation), etc. are illustrated. Moreover, XRD-7700 (made by Shimadzu Corporation.), RINT2200Ultima + / PC (made by Rigaku Corporation), etc. are illustrated as a measuring apparatus of a parallel-beam optical system.

Moreover, when the amount of present compound 1 in a formulation should be measured, it is preferable to use HPLC normally. That is, for example, a calibration curve is prepared by measuring by HPLC using a standard product of Compound 1 of known chemical purity, which is known as Compound 1, and the amount of Compound 1 present in the sample is quantified based on the calibration curve. can do.

The quantitative method by HPLC and the measuring method of the crystal | crystallization concerning the compound 1 mentioned above are similarly applicable also to this compound 2 or this compound 3 mentioned later. For example, as HPLC conditions, it can carry out on the same conditions as the above, and the measuring method by differential scanning calorimetry can also be measured using the characteristic endothermic peak in each. In addition, each crystal purity can be measured and calculated in the same manner as described above. The pure Form A crystals or Form B crystals of Compound 1 which are used as a reference product in the above-mentioned measurement and the seed crystals used in the production method of the crystals described later are purely Form A crystals or Form B crystals of Compound 1 Are obtained according to the respective methods of Examples 3, 4 or 5 of the present application, respectively, by selecting a crystal having a particularly preferable shape, and by selecting a crystal showing a single endothermic peak characteristic by differential scanning calorimetry, respectively. Each can be obtained. Moreover, it is also possible to use the B type crystal acquired by each method of Examples 6-7 as a standard product. Moreover, it is also possible to use the B type crystal acquired by each method of Examples 6-7 as seed crystal for acquiring pure B type crystal. By the way, when type B crystal | crystallization mixes with a type | mold crystal | crystallization, the quantitative value of the type A crystal by differential scanning calorimetry may be measured slightly lower than the quantitative value of the normal standard type A crystal. The degree varies depending on the incorporation rate of the B crystal relative to the A crystal, but for example, if the incorporation ratio of the B crystal is within 10%, the quantitative value of the A crystal may be about 10% error. . Moreover, when the mixing ratio of type B crystals is close to 50%, there may be an error of up to about 20%. On the contrary, in the case where the A-type crystal is mixed in the B-type crystal, the quantitative value may be measured slightly higher than the standard B-type crystal, and it changes depending on the mixing ratio of the A-type crystal to the B-type crystal. For example, if the incorporation rate of the Form A crystal is less than 10%, the quantitative value of the Form B crystal may be an error of about 10%, and if the incorporation rate of the Form A crystal is close to 50%, about 20% at most. There is a possibility of error. In particular, in a normal state in which the mixing ratio of each other is not high, the crystal purity of the A-type crystal or the B-type crystal may include an error of about 10%. In the case of quantification, there is a method of preparing and quantifying a calibration curve by a standard product of expected mixing ratio. In addition, in order to judge the mixing ratio more clearly, a mixture having a known mixing ratio of the A-type crystal standard and the B-type crystal standard is appropriately prepared, and based on the mixing ratio (percentage) of the problem crystal and melting of the crystal. A calibration curve is created from a percentage of the total peak area of the area (mJ) of the endothermic peak, and the mixing ratio of the crystals in the test object can be known from the calibration curve.

In addition, measurement methods other than differential scanning calorimetry, i.e., measurement methods such as powder X-ray diffraction spectrum, infrared absorption spectrum, solid ¹³ C-NMR spectrum, and Raman spectrum, are also determined by a calibration curve using a standard mixture having a known mixing ratio. In this case, the mixing ratio can be judged more clearly.

1 is a powder X-ray diffraction spectrum of Compound 2 crystals. In the figure, the vertical axis represents intensity (CPS), and the horizontal axis represents 2θ (°).

2 is a powder X-ray diffraction spectrum of Compound 3 crystals. In the figure, the vertical axis represents intensity (CPS), and the horizontal axis represents 2θ (°).

3 is a powder X-ray diffraction spectrum of Form A crystals of Compound 1; In the figure, the vertical axis represents intensity (CPS), and the horizontal axis represents 2θ (°).

4 is a differential scanning calorimetry of Form A crystals of Compound 1; In the figure, the vertical axis represents mW, and the horizontal axis represents temperature (° C).

5 is an infrared absorption spectrum of Form A crystals of Compound 1; In the figure, the vertical axis represents transmittance (%) and the horizontal axis represents cm ⁻¹ .

6 is a powder X-ray diffraction spectrum of Form B crystal of Compound 1; In the figure, the vertical axis represents intensity (CPS), and the horizontal axis represents 2θ (°).

7 is a differential scanning calorimetry of Form B crystals of Compound 1; In the figure, the vertical axis represents mW, and the horizontal axis represents temperature (° C).

8 is an infrared absorption spectrum of Form B crystals of Compound 1; In the figure, the vertical axis represents transmittance (%) and the horizontal axis represents cm ⁻¹ .

9 shows a calibration curve in differential scanning calorimetry of Form A crystals of Compound 1; In the figure, the vertical axis represents area (mJ), and the horizontal axis represents weight (mg).

10 shows a calibration curve in differential scanning calorimetry of Form B crystals of Compound 1; In the figure, the vertical axis represents area (mJ), and the horizontal axis represents weight (mg).

FIG. 11 is a drawing substitute photograph showing a crystal shape of Form A crystals of Compound 1, a scanning electron microscope (SEM) photograph. FIG.

FIG. 12 is a drawing substitute photograph showing a crystal shape of Form B crystal of Compound 1 as a scanning electron microscope (SEM) photograph. FIG.

[Method for producing Form A crystals of Compound 1]

As a manufacturing method of the Form A crystal of this compound 1, the method of adding an acid to the solution under basic conditions of this compound 1, producing the crystal which consists of this compound 1, and obtaining a crystal | crystallization is mentioned.

That is, the solution under basic conditions of Compound 1 used in the present invention is not particularly limited as long as the compound is a solution dissolved under basic conditions. Here, the compound to be dissolved may be an oil phase or a solid phase (various crystalline or amorphous forms). Or mixtures thereof. The compound 1 can be prepared according to the method of WO 03/70686.

As a base used for preparing the solution under basic conditions mentioned above, an inorganic base is preferable. That is, alkali metal bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium t-butoxide, etc. are mentioned, for example, sodium hydroxide, potassium hydroxide, etc. are preferable, and sodium hydroxide is preferable. Particularly preferred examples may be mentioned. These may be used in the form of water or a solution such as alcohols such as methanol, ethanol, t-butanol, or the like. When preparing and using an aqueous solution containing a predetermined concentration of base in advance, it is easy to define the amount to be added. Especially preferred. Moreover, when a thick basic solution is used, since the case where high heat of neutralization generate | occur | produces when acid is added afterwards can be considered, the case where an aqueous solution of 0.5-2 regular bases is used is a very preferable example.

As a minimum, the amount of the base to add is 0.8 equivalent or more normally with respect to 1 equivalent of compounds, Preferably it is 0.9 equivalent or more, More preferably, 1.0 equivalent or more is illustrated. As an upper limit, 3.0 equivalent or less is illustrated normally with respect to 1 equivalent of compounds, and 2.0 equivalent or less is mentioned as a preferable example.

As a solvent used for dissolving a compound together with a base, Preferably, a polar solvent is mentioned, Specifically, Alcohol, such as water, methanol, ethanol, Ether, such as tetrahydrofuran, a dioxane, Acetone, etc. are mentioned. These can be mentioned and these can be mixed and used as needed. Of these, water, methanol, ethanol, tetrahydrofuran and the like are preferable, and water, methanol, ethanol and the like are particularly preferable. Moreover, it is very preferable to mix and use water and methanol, and the ratio of water: methanol after making it the solution containing a base is illustrated 1: 20-10: 1, but the ratio of 1: 10-1: 1 is preferable. Do.

In the solution under basic conditions mentioned above, you may warm up to the temperature below the boiling point of a solvent, and when an insoluble matter exists, it is preferable to remove an insoluble matter by operation, such as filtration.

The acid to be added to the solution may be in any of liquid, solid and gas phases, as long as it is not introduced into the precipitate of crystals generated by adding the acid. Preferably, the acid is in solution or gas. Particularly preferred examples may be mentioned.

In addition, various kinds of organic acids and inorganic acids may be used. However, in order to neutralize the base, the acid to be used needs to have a higher acidity than the acidity of the compound. Thus, mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid are preferable, and hydrochloric acid is particularly preferable. These may be used in the form of water or a solution such as alcohols such as methanol, ethanol, t-butanol, or the like. In the case of preparing and using an aqueous solution containing an acid of a predetermined concentration in advance, it is easy to define the amount to be added. desirable. Moreover, since the case where a high heat of neutralization generate | occur | produces when a thick acidic solution is used, the case where an acidic aqueous solution of 0.5-2 prescription is used is especially preferable example.

The amount of acid to be added may be added to the extent that crystals are sufficiently formed, and is not particularly limited. Usually, 0.8 equivalent or more is usually exemplified with respect to 1 equivalent of base, and preferably 0.9 equivalent or more is preferably added. Do. Moreover, it is especially preferable to add about 1 equivalent. Moreover, although it does not specifically limit as an upper limit, 1.5 equivalent or less is illustrated normally with respect to 1 equivalent of base, and 1.2 equivalent or less is mentioned as a preferable example.

As the method of adding an acid, (1) adds at once, (2) adds several times, and (3) adds over time continuously by the method of dripping, etc., but the method of dripping etc. The method of adding time continuously is preferable. It is preferable to carry out stirring when adding an acid. The rate of addition varies depending on the amount of the compound used, the concentration of the base in the solution under basic conditions, the type of acid used, and the concentration of the acidic solution. However, when 0.5 to 2 hydrochloric acid is used, it is 1 to 6 hours. The method of adding whole quantity over is illustrated.

As for the temperature at the time of adding an acid, 60 degrees C or less is preferable as an upper limit, 50 degrees C or less is more preferable, 45 degrees C or less is still more preferable, 0 degrees C or more is preferable as a minimum, and 10 degrees C or more is more preferable. Preferably, 25 degreeC or more is more preferable.

In acquiring the produced crystals, it is usually exemplified to perform within 24 hours, preferably within 20 hours, particularly preferably within 10 hours after addition of the acid. Moreover, although crystal | crystallization can also be acquired immediately after addition of an acid, It is preferable to carry out after 1 hour after addition, Especially preferably, after 3 hours after addition.

Although the crystal | crystallization can be acquired by well-known methods, such as filtration and a decant, as a collection method of the precipitated crystal | crystallization, it is preferable to filter normally. After the crystals have been collected by filtration, the crystals can be washed with a polar solvent such as water, methanol, ethanol or a mixture thereof, which is effective as an operation for removing impurities. As a washing | cleaning method, the method of rinsing the crystal | crystallization on a filter with a polar solvent is preferable. In addition, a method in which the crystals are added to a polar solvent such as water, methanol, ethanol or a mixture thereof to form a suspension, and after sufficiently stirring the crystals, crystals are again obtained by filtration is also preferable. Moreover, it is especially preferable to perform both said washing | cleaning. The collected crystal can be dried by a drying method usually performed, for example, vacuum drying, vacuum heating, drying, atmospheric pressure drying, wind drying, or the like.

As the concentration of the final compound after the acid is added, depending on the type of solvent used and the mixed solvent, the ratio is generally 1 w / v% or more, preferably 5 w / v% or more. Can be mentioned. As an upper limit, 30w / v% or less is preferable and 20w / v% or less is a preferable example.

When producing crystals, it is also considered a preferred form to add a small amount of A crystals as seed crystals.

The following is illustrated as a preferable example of the said manufacturing method. In the examples of the following three production methods, the amount of the base to be used, the stirring temperature before acid addition, the amount of acid to be added, and the stirring time after acid addition can adopt the above-described preferred examples.

0.8-3.0 equivalents of sodium hydroxide or potassium hydroxide relative to 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid An aqueous solution of hydrochloric acid, sulfuric acid, or phosphoric acid containing 0.8 to 1.5 equivalents to 1 equivalent of base, at a temperature of 10 to 50 ° C. under stirring, in a solution dissolved in water, methanol, ethanol, tetrahydrofuran, or a mixed solvent thereof. The method is continuously added to the solution by dropping or the like, and stirred for further 1 to 24 hours to obtain crystals.

Further, to a solution dissolved in water, methanol, ethanol or a mixed solvent thereof containing 0.9 to 2.0 equivalents of sodium hydroxide relative to 1 equivalent of the compound, at a temperature of 25 to 45 ° C with respect to 1 equivalent of base 0.9-1.2 equivalents of 0.5-2 normal hydrochloric acid aqueous solution are added over 1 hour to 6 hours, and further stirred for 3 to 24 hours to obtain crystals.

Also, 0.9 to 1.2 equivalents of the base was added to the solution dissolved by adding 0.9 to 2.0 equivalents of 0.5-2 normal sodium hydroxide aqueous solution and methanol to 1 equivalent of the compound, and stirred at a temperature of 25 to 45 ° C. A 0.5-2 normal hydrochloric acid aqueous solution is added over 1 hour to 6 hours, and further stirred for 3 to 24 hours to obtain crystals.

Moreover, as a solution under the basic conditions of the compound 1 mentioned above, 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl- 1H-indazol-5-yl) phenyl ] Alkali hydrolyzate of lower alkyl ester of propionic acid may be sufficient. That is, the following is mentioned as another manufacturing method of A-type crystal | crystallization.

The lower alkyl ester of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid is subjected to alkali hydrolysis in a solvent, It is a method of obtaining a crystal | crystallization by adding an acid to the solution under basic conditions.

As said "lower alkyl ester", the carboxylic acid ester of a C1-C4 alkyl group is illustrated, As a C1-C4 alkyl group, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, Any of isobutyl group, sec-butyl group, and t-butyl group is represented. Of these, methyl and ethyl groups are particularly preferred examples.

Lower alkyl esters of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid are described in WO 03/70686. It may be prepared according to the method of a call.

As a base used when preparing the alkali hydrolyzate of the said compound, the base used in order to make the above-mentioned solution into basic conditions can be used.

As for the usage-amount of a base, 1 equivalent or more is normally illustrated with respect to 1 equivalent of compounds. As an upper limit, 10 equivalent or less is normally illustrated with respect to 1 equivalent of compounds, 3 equivalent or less is preferable, and 2 equivalent or less is mentioned as a particularly preferable example.

The solvent is preferably reacted in an inert medium, preferably a polar solvent, which does not interfere with the reaction. Although the conditions mentioned above can also be referred to, water, methanol, ethanol, tetrahydrofuran, dioxane, etc. are mentioned as a polar solvent, These can be mixed and used as needed. Of these, water, methanol, ethanol, tetrahydrofuran and the like are preferable, and water, methanol, ethanol and the like are particularly preferable. Moreover, when mixing water and methanol, it is very preferable. As a reaction solution after adding a base, the mixing ratio of water: methanol is illustrated as 1: 20-10: 1, but the ratio of 1: 10-1: 1 desirable.

Moreover, as reaction temperature of alkali hydrolysis, the suitable temperature from room temperature to the reflux temperature of a solvent is selected, for example, The conditions of 50-70 degreeC are mentioned especially preferable. Reaction time is 0.5-72 hours normally, Preferably 1-24 hours are illustrated, More specifically, as an upper limit, 24 hours or less are preferable, 20 hours or less are more preferable, and 10 hours or less are furthermore Preferably, the lower limit is preferably 0.5 hours or later, more preferably 1 hour or later, and even more preferably 3 hours or later, but the reaction progress is tracked by thin layer chromatography (TLC), high performance liquid chromatography (HPLC) or the like. Since it is possible, the quantity of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid becomes the largest What is necessary is just to terminate reaction suitably at a point.

After the alkali hydrolysis reaction, the conditions for producing an acid, crystals, and the extraction method which are added to the solution under basic conditions are as described above.

The following is illustrated as a preferable example of the said manufacturing method. In the examples of the following three production methods, the amount of base to be used in alkaline hydrolysis, the reaction temperature of the hydrolysis reaction, the reaction time of the hydrolysis reaction, the stirring temperature before acid addition, the amount of acid to be added and after acid addition The stirring time can adopt the above-mentioned preferable example.

Lower alkyl esters of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid are added with water, methanol, ethanol, tetrahydro After reacting for 1 to 24 hours at 50-70 degreeC with 1 equivalent of sodium hydroxide or potassium hydroxide with respect to 1 equivalent of lower alkyl esters in furan or these mixed solvents, the temperature of 10-50 degreeC under stirring A method in which 0.8-1.5 equivalents of an aqueous solution of hydrochloric acid, sulfuric acid or phosphoric acid is added continuously by dropping or the like with respect to 1 equivalent of base, followed by further stirring for 1 to 24 hours to obtain crystals.

In addition, methyl or ethyl ester of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid is added to water, methanol or ethanol. Or 1 to 2 equivalents of sodium hydroxide in the presence of 1 to 2 equivalents of methyl or ethyl ester in these mixed solvents and reacted at 50 to 70 ° C. for 1 to 24 hours, followed by stirring at a temperature of 25 to 45 ° C. to the base. 0.9-1.2 equivalents of 0.5-2 normal hydrochloric acid aqueous solution is added over 1 hour to 6 hours, and further stirred for 3 to 24 hours to obtain crystals.

Further, methyl or ethyl ester of methyl or ethyl ester of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid 1 to 2 equivalents of 0.5-2 normalized sodium hydroxide aqueous solution and methanol were added per 1 equivalent and reacted at 50 to 70 ° C. for 1 to 24 hours, followed by stirring at a temperature of 25 to 45 ° C., 0.9 per 1 equivalent of base. A method in which a 1.2-2 equivalent hydrochloric acid aqueous solution of ˜1.2 equivalents is added over 1 hour to 6 hours, followed by further stirring for 3 to 24 hours to obtain crystals.

[Production method of Form B crystal of Compound 1]

As a method for producing Form B crystals of Compound 1, Compound 1 is dissolved in any one or two or more solvents selected from the group consisting of acetone, dichloromethane, methanol, ethyl acetate, methanol / acetic acid mixture, and acetonitrile. The method of crystallizing from a solution is mentioned.

As described above, Compound 1 can be prepared according to the method of International Publication WO 03/70686 and the like.

Moreover, as a solvent used above, acetone, dichloromethane, methanol, ethyl acetate, acetonitrile, tetrahydrofuran, diisopropyl ether, nitrobenzene, 2,2, 2- trifluoro ethanol, N, N- Dimethylformamide, N, N-dimethylacetamide, etc. are mentioned, These solvent can also be mixed and used. In addition, tetrahydrofuran / water, N, N-dimethylformamide / water, N, N-dimethylacetamide / water, tetrahydrofuran / methanol, diisopropyl ether / acetic acid, methanol / acetic acid and the like can be mentioned. Of these, acetone, dichloromethane, methanol, ethyl acetate, acetonitrile, methanol / acetic acid and the like are preferred, and acetone, dichloromethane and the like are particularly preferred.

When dissolving a compound in a solvent, it is preferable to warm it to the temperature below the boiling point of a solvent by the point of the quantity of crystal | crystallization obtained, etc. Moreover, when an insoluble matter exists, you may remove an insoluble matter by operation, such as filtration.

The amount of the solvent to be added varies depending on the kind of the solvent to be used and the mixed solvent, depending on the ratio, but the amount at which the compound is dissolved at a temperature below the boiling point of the solvent used is preferable, and the amount of the solvent to be obtained may be Particular preference is given to using an amount in which the compound dissolves to a saturated concentration near the boiling point. Specifically, for example, when acetone is used as the solvent, 15 to 25 ml is preferable for 1 g of the compound, and about 15 ml is more preferable. Moreover, when dichloromethane is used, it is preferable to use the quantity of 30-50 ml with respect to 1 g of compounds, and about 30 ml is mentioned as a more preferable example.

As a method of cooling the solution of the compound prepared by heating, the method of cooling rapidly, cooling stepwise, cooling, etc. is mentioned, The method of cooling stepwise or the method of cooling is preferable.

The cooling temperature varies depending on the amount of the solvent used, the kind of the solvent used, and the mixed solvent, depending on the ratio, and also depending on the temperature at the time of dissolving the compound. It is preferable.

Although cooling operation may be performed while stirring, and may be performed by standing still, it is preferable to carry out, stirring, in the point which accelerates precipitation of a crystal | crystallization and shortens an operation time.

Moreover, when producing crystal | crystallization by the said method, it is also a preferable aspect to add a small amount of B crystal | crystallization as seed crystal | crystallization.

Generally, the precipitated crystals can be collected by filtration. After the crystals are collected by filtration, the crystals can be washed with a solvent used for dissolving the compound or a solvent that does not significantly dissolve the crystals, or a mixture thereof, which is effective as an operation for removing impurities.

The collected crystal can be dried by a drying method usually performed, for example, vacuum drying, vacuum heating, drying, atmospheric pressure drying, wind drying, or the like.

The following is illustrated as a preferable example of the said manufacturing method.

To 1 g of Compound 1, 15 to 25 ml of acetone or 30 to 50 ml of dichloromethane are added, and heated to near the boiling point to dissolve the compound. If necessary, the insolubles are filtered and then stirred at room temperature. A method of obtaining a crystal produced after several hours to several days.

Moreover, as another manufacturing method regarding Form B crystal of this compound 1, Form B crystal of this compound 1 is just before compound 1 starts to crystallize in the process of adding an acid to the solution of the compound 1 under basic conditions. Is added as seed crystal, and the method of producing | generating a crystal | crystallization by producing | generating Form B crystal of this compound 1 is also mentioned.

The compound 1, the shape, and the method of obtaining the compound used for this invention are the same as the description in the term of the "manufacturing method of the A-type crystal of this compound 1" mentioned above. Moreover, the preparation method of the solution under basic conditions of this compound 1 is the same as the above. In addition, the solution under the basic conditions described above is a lower alkyl ester of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid The alkali hydrolyzate may be the same as above.

The kind and amount of the acid to be added, such as the kind and amount of the base used for preparing the solution under the basic conditions described above, the kind and amount of the solvent used to dissolve the compound together with the base, and the method of adding the acid, The above description can also apply mutatis mutandis to the rate of addition, the temperature at the time of addition, and the like. As a method of adding seed crystals of type B crystals, it is preferable that crystals do not exist in the mixed liquid in the step of adding seed crystals, and it is preferable that the added seed crystals are present without being dissolved. When an acid is added after adding and dissolving a base equivalent or more of the compound and dissolving it, in the step of neutralizing with an acid to which the base is added or equivalent, adding seed crystals of type B crystals avoids dissolution of seed crystals. desirable. In addition, it is also a preferable method at this time to confirm neutralization of the base equivalent or more using an instrument by a pH meter etc. That is, for example, in the case of dissolving the compound using 1.5 equivalents of base with respect to the compound, 0.5 equivalent of acid is added, and seed crystals are added at a stage in which the pH in the system shows weak basicity of about 7-9. It is a preferable example to do. In addition, seed crystals are preferably added before crystals are formed by addition of an acid. When adding 2 hydrochloric acid over 1 hour to 6 hours, after neutralization of the base equivalent or more of the above-mentioned compound is complete | finished, in the step which pH in-system shows weak acidity by addition of 0.1-0.2 equivalent acid, Since it is highly likely that crystals will start to form, it is preferable to perform seed crystal addition of Form B at a stage earlier than this.

The amount of Form B crystals to be added may be an amount in which the added crystals do not dissolve, and are not particularly limited, but are usually 0.01% or more to the compound, preferably 0.05% or more, and particularly preferably about 0.1%. The addition of% is illustrated. Moreover, although it does not specifically limit as an upper limit, Usually 2% or less is illustrated with respect to a compound, Preferably it is 1.5% or less, More preferably, it is 1.0% or less, Especially preferably, 0.3% or less is illustrated. As for the method of collecting the precipitated crystals, the method of drying the collected crystals, the concentration of the final compound after adding the acid, and the like, the same conditions as in the above-described method for producing the Form A crystals of Compound 1 can be used. have.

The following is illustrated as a preferable example of the said manufacturing method. In the examples of the following three production methods, the amount of base to be used, the stirring temperature before acid addition, the amount of acid to be added, the amount of seed crystals to be added to B, and the stirring time after acid addition are given in the preferred examples described above. Can be adopted.

This solution contains 10 to 50 DEG C while stirring in a solution dissolved in water, methanol, ethanol, tetrahydrofuran or a mixed solvent thereof containing 0.8 to 3.0 equivalents of sodium hydroxide or calcium hydroxide per 1 equivalent of Compound 1. At a temperature, 0.8-1.5 equivalents of an aqueous solution of hydrochloric acid, sulfuric acid or phosphoric acid is continuously added to the equivalent of base by the dropwise method, etc., and the pH in the system shows a weak basicity of 7-9. After adding 0.01-2% of seed crystal of a type with respect to a compound, it is stirred for further 1 to 24 hours and a crystal is obtained.

Moreover, 1 equivalent of base is stirred at the temperature of 25-45 degreeC with stirring in the solution dissolved in water, methanol, ethanol, or these mixed solvent containing 0.9-2.0 equivalent sodium hydroxide with respect to 1 equivalent of compound 1 0.9-1.2 equivalents of 0.5-2 prescribed hydrochloric acid aqueous solution were added over 1 hour to 6 hours, and the seed crystals of type B were formed in 0.05 to about compound at the stage in which pH in the system showed weak basicity of 7-9. After adding 1.5%, the method is further stirred for 1 to 5 hours to obtain crystals.

In addition, 0.9-2.0 equivalents of 0.5-2 normal sodium hydroxide aqueous solution and methanol are added with respect to 1 equivalent of the compound 1, and it is 0.9-1.2 with respect to 1 equivalent of base at the temperature of 25-45 degreeC under stirring at the solution which melt | dissolved. 1 equivalent of 0.5-2 hydrochloric acid aqueous solution was added over 1 hour to 6 hours, and 0.1% of seed B crystals were added to the compound in a step in which pH in the system showed a weak basicity of 7-9. A method of obtaining crystals by further stirring for 5 hours.

Moreover, the following aspects are also illustrated as a preferable example of a manufacturing method. In the examples of the following three production methods, the amount of base used in alkali hydrolysis, the reaction temperature of the hydrolysis reaction, the reaction time of the hydrolysis reaction, the stirring temperature before acid addition, the amount of acid to be added, and the amount of B added The amount of seed crystals of the mold and the stirring time after acid addition can adopt the above-mentioned preferred examples.

Lower alkyl esters of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid are added with water, methanol, ethanol, tetrahydro After reacting for 1 to 24 hours at 50-70 degreeC with 1 equivalent of sodium hydroxide or potassium hydroxide with respect to 1 equivalent of lower alkyl esters in furan or these mixed solvents, the temperature of 10-50 degreeC under stirring In the step of adding 0.8-1.5 equivalents of an aqueous solution of hydrochloric acid, sulfuric acid or phosphoric acid to the equivalent of base in a continuous manner such as dropwise addition, in the step of pH in the system showed a weak basicity of 7-9 After adding 0.01-2% of the seed crystals with respect to the compound, the mixture is further stirred for 1 to 24 hours to obtain crystals.

In addition, methyl or ethyl ester of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid is added to water, methanol or ethanol. Or 1 to 2 equivalents of sodium hydroxide in the presence of 1 to 2 equivalents of methyl or ethyl ester in these mixed solvents and reacted at 50 to 70 ° C. for 1 to 24 hours, followed by stirring at a temperature of 25 to 45 ° C. to the base. 0.9-2. 2 equivalents of 0.5-2 hydrochloric acid aqueous solution were added over 1 hour to 6 hours, and the seed crystals of Form B were prepared at 0.05-1.5 with respect to the compound in the stage where pH in the system showed weak basicity of 7-9. After adding%, the method is further stirred for 3 to 24 hours to obtain crystals.

Further, methyl or ethyl ester of methyl or ethyl ester of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid 1 to 2 equivalents of 0.5-2 normalized sodium hydroxide aqueous solution and methanol were added per 1 equivalent and reacted at 50 to 70 ° C. for 1 to 24 hours, followed by stirring at a temperature of 25 to 45 ° C., 0.9 per 1 equivalent of base. After adding 1.2 equivalents of 0.5-2 hydrochloric acid aqueous solution over 1 hour to 6 hours and adding 0.1% of seed crystals of type B to the compound at the stage in which pH in the system showed weak basicity of 7-9 And further stirring for 3 to 24 hours to obtain crystals.

[Method for producing Crystal of Compound 2]

In addition, the crystal of the compound 2 of the present invention has a large advantage in the formulation process such as it is easy to make the content of the compound of each formulation uniform, and the crystal is easier to remove the solvent than the case of an oily substance. It is advantageous in that it is advantageous to obtain a compound of good purity without performing purification by column chromatography in the above-described known production method by finding a method for producing a crystal, and also for industrial scale production. It is suitable and very preferable.

As a manufacturing method of the crystal of the compound 2, the method which obtains the crystal | crystallization by adding the poor solvent which is hard to dissolve a compound to the solution prepared by melt | dissolving in the subsolvent which is easy to melt | dissolve compound 2 is prepared, and obtaining a crystal. Can be mentioned. Compound 2 can be prepared according to the method of WO 03/70686.

Toluene, ethyl acetate, tetrahydrofuran, acetone, dimethoxyethane, methanol, etc. are mentioned as a subsolvent used for melt | dissolution of a compound, but acetone, toluene, tetrahydrofuran, etc. are preferable and acetone is especially preferable. . Moreover, heptane, diisopropyl ether, isopropanol, t-butyl methyl ether, water, etc. are mentioned as a poor solvent which can be added in order to produce | generate a crystal of a compound, However, when acetone is used as a subsolvent, Preferably, heptane is preferable when toluene or tetrahydrofuran is used as the subsolvent. The combination which uses acetone as an auxiliary solvent and water as a poor solvent is especially preferable example.

As a density | concentration of the solution prepared with a subsolvent, it is preferable that it is 20 w / v% or less as an upper limit, It is more preferable that it is 10 w / v% or less, It is preferable that it is 5 w / v% or more as a minimum. The upper limit of the amount of the poor solvent added is preferably 2.0 times or less, more preferably 1.5 times or less, still more preferably 1.1 times or less, further preferably 0.8 times or more, and 0.9 times the lower limit relative to the subsolvent. The above is more preferable. In particular, it is preferable to add 1.0-fold amount. There are other forms in which it is particularly desirable to add 1.05 times more. As a poor solvent addition method, the method of adding over time continuously by methods, such as dripping, is preferable. When adding a poor solvent, it is preferable to carry out stirring. The rate of addition varies depending on the amount of the compound used, the concentration of the compound in the solution, the type of the subsolvent to be used, and the type of the poor solvent, but when water is added to the acetone solution of the compound as the poor solvent, it is 1 to 3 hours. A method of adding over is illustrated.

As for the temperature at the time of adding a poor solvent, 50 degrees C or less is preferable as an upper limit, 40 degrees C or less is more preferable, 30 degrees C or less is more preferable, As a minimum, 0 degrees C or more is preferable, and 10 degrees C or more is More preferably, 20 degreeC or more is more preferable.

In obtaining the resulting crystals, it is usually exemplified to carry out within 1 hour after the addition of the poor solvent, within 24 hours, preferably after 1 hour and within 5 hours.

Although the crystal | crystallization can be acquired by well-known methods, such as filtration and a decant, as a collection method of the precipitated crystal | crystallization, it is preferable to filter normally. After the crystals have been collected by filtration, the crystals can be washed with a polar solvent such as water, acetone or a mixture thereof, which is effective as an operation for removing impurities.

The collected crystal can be dried by a drying method usually performed, for example, vacuum drying, vacuum heating, drying, atmospheric pressure drying, wind drying, or the like.

[Method for producing Crystal of Compound 3]

In addition, the crystal of the compound 3 of the present invention has a large advantage in the formulation process, such as it is easy to uniformize the content of the compound of each agent, and the crystal is easier to remove the solvent than the case of the oil. It is advantageous at one point and also has the advantage of obtaining a compound of good purity without performing purification by column chromatography in the above-mentioned known manufacturing method by finding a method for producing a crystal, and suitable for industrial scale production. It is very desirable.

As a method for producing a crystal of Compound 3, a method of obtaining a crystal by adding a poor solvent that is difficult to dissolve the compound to a solution prepared by dissolving it in a subsolvent which Compound 3 is easy to dissolve, to produce a crystal, Can be mentioned.

This compound 3 can be prepared according to the method of WO 03/70686. Moreover, 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid is acidic conditions, for example in methanol solvent. It can also be prepared using normal methyl esterification reaction, such as methyl esterification under.

Although toluene, ethyl acetate, tetrahydrofuran, acetone, etc. are mentioned as a subsolvent used for melt | dissolution of a compound, Acetone, tetrahydrofuran, etc. are preferable, and tetrahydrofuran is especially preferable. Moreover, although heptane, isopropanol, methanol, water, etc. are mentioned as a poor solvent, Water or heptane is preferable when using acetone as a subsolvent, and heptane and isopropanol when tetrahydrofuran is used as a subsolvent. , Water is preferred. The combination which uses tetrahydrofuran as an subsolvent and water as a poor solvent is especially preferable example.

As a density | concentration of the solution prepared with a subsolvent, it is preferable that it is 20 w / v% or less as an upper limit, It is more preferable that it is 10 w / v% or less, It is preferable that it is 5 w / v% or more as a minimum. The upper limit of the amount of the poor solvent added is preferably 2.0 times or less, more preferably 1.5 times or less, still more preferably 1.1 times or less, further preferably 0.8 times or more, and 0.9 times the lower limit relative to the subsolvent. The above is more preferable. In particular, it is preferable to add 1.0-fold amount. There are also other forms in which it is particularly preferable to add 1.05 times the amount. As a poor solvent addition method, the method of adding over time continuously by the method of dripping etc. is preferable. When adding a poor solvent, it is preferable to carry out stirring. The rate of addition varies depending on the amount of the compound used, the concentration of the compound in the solution, the subsolvent used, and the kind of the poor solvent. However, when water is added as a poor solvent to the tetrahydrofuran solution of the compound, it is from 1 hour. The method of addition over 3 hours is illustrated.

As for the temperature at the time of adding a poor solvent, 50 degrees C or less is preferable as an upper limit, 40 degrees C or less is more preferable, 35 degrees C or less is more preferable, As a minimum, 0 degrees C or more is preferable, and 10 degrees C or more is More preferably, 25 degreeC or more is more preferable.

When obtaining the produced crystal | crystallization, the acquisition of a crystal | crystallization is usually performed within 1 hour, within 24 hours, Preferably after 1 hour and within 5 hours under ice-cooling after addition of a poor solvent.

Although the crystal | crystallization can be acquired by well-known methods, such as filtration and a decant, as a collection method of the precipitated crystal | crystallization, it is preferable to filter normally. After the crystals have been collected by filtration, the crystals can be washed with a polar solvent such as water, acetone or a mixture thereof, which is effective as an operation for removing impurities.

The collected crystal can be dried by a drying method usually performed, for example, vacuum drying, vacuum heating, drying, atmospheric pressure drying, wind drying, or the like.

The compound inhibits oral inflammatory edema, allergic edema, acetic acid rising reaction and adjuvant arthritis in rats by oral administration of 0.1 to 500 mg / kg, while the mice are orally administered 500 mg / kg / day for 3 days. It is a compound that is safe as a medicament in a mammal, preferably a pet, a companion animal or a domestic animal such as a human, a dog or a cat, or the like, since it has not been confirmed death. Pharmaceuticals in mammals, preferably pets, pets, such as humans, dogs or cats, or domestic animals, may exhibit a variety of acute or chronic inflammatory reactions resulting from the production of prostaglandins and / or leukotrienes, various diseases or conditions, ie Preferred examples include any of inflammatory diseases, allergic diseases, autoimmune diseases, and prophylactic and / or therapeutic drugs for pain.

In order to use the compound as the medicament, an effective amount of the compound may be used as it is or by mixing with a pharmaceutically acceptable carrier to form a pharmaceutical composition. As the carrier, for example, suspending agents such as carboxymethyl cellulose and other known compounds Carriers may also be used. As an example, the method of suspending and using the compound of this invention in the purified water containing 0.5% carboxymethylcellulose is mentioned.

Tablets, powders, granules, syrups, suspensions, capsules, injections and the like may be used as formulations for the formulation of the pharmaceutical compositions. However, when the properties of the crystals of the compound are considered, the pharmaceutical compositions are dry preparations. Particularly preferred. For the preparation, various carriers according to these formulations are used. For example, as a carrier of an oral preparation, an excipient, a binder, a lubricant, a fluidity promoter, and a coloring agent are mentioned.

When the compound of the present invention is used as a parenteral such as an injection, diluent, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, and the like can be generally used. Moreover, you may add a fungicide, an antiseptic | preservative, a stabilizer, an isotonicity agent, a painless agent, etc. as needed.

When the compound of the present invention is administered to a mammal, for example, a human, it can be administered orally in the form of tablets, powders, granules, suspensions, capsules, and further includes injections containing drops, further suppositories, gels, lotions, Parenteral administration may be in the form of ointments, creams or sprays. The dosage varies depending on the application, the dosage form, the age, the weight of the patient, the degree of symptoms, and the like, but in general, administration of 1 to 1000 mg once or three times per adult is exemplified. The administration period is generally several days to two months of daily administration, but depending on the patient's symptoms, both daily dose and duration of administration can be increased or decreased.

Moreover, although the following compound is mentioned as a similar compound of this compound, these compounds can also be manufactured according to the method of international publication WO03 / 70686, or by the manufacturing method described in this specification.

3- [3-amino-4- (indan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-5- (1-ethyl-1 H-indazol-5-yl) 4- (indan-2-yloxy) phenyl] propionic acid;

3- [4- (Indan-2-yloxy) -3- (N-methylamino) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid;

3- [4- (Indan-2-yloxy) -5- (1H-indazol-5-yl) -3- (N-methylamino) phenyl] propionic acid;

3- [5- (1-ethyl-1H-indazol-5-yl) 4- (indan-2-yloxy) -3- (N-methylamino) phenyl] propionic acid;

3- [3-amino-4- (4-fluoroindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5-fluoroindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-difluoroindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-4- (1-hydroxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (4-hydroxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5-hydroxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-dihydroxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-4- (4-methoxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5-methoxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-dimethoxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-4- (4-benzyloxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (4-benzyloxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-dibenzyloxyindan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-4- (4-fluoroindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5-fluoroindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-difluoroindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-4- (1-hydroxyindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (4-hydroxyindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5-hydroxyindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-dihydroxyindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-5- (1H-indazol-5-yl) -4- (4-methoxyindan-2-yloxy) phenyl] propionic acid and isomers;

3- [3-amino-5- (1H-indazol-5-yl) -4- (5-methoxyindan-2-yloxy) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-dimethoxyindan-2-yloxy) -5-(-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-4- (4-benzyloxyindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (4-benzyloxyindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-dibenzyloxyindan-2-yloxy) -5- (1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-5- (1-ethyl-1 H-indazol-5-yl) -4- (4-fluoroindan-2-yloxy) phenyl] propionic acid and isomers;

3- [3-amino-5- (1-ethyl-1 H-indazol-5-yl) -4- (5-fluoroindan-2-yloxy) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-difluoroindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-5- (1-ethyl-1 H-indazol-5-yl) -4- (1-hydroxyindan-2-yloxy) phenyl] propionic acid and isomers;

3- [3-amino-5- (1-ethyl-1 H-indazol-5-yl) -4- (4-hydroxyindan-2-yloxy) phenyl] propionic acid and isomers;

3- [3-amino-5- (1-ethyl-1 H-indazol-5-yl) -4- (5-hydroxyindan-2-yloxy) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-dihydroxyindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-5- (1-ethyl-1 H-indazol-5-yl) -4- (4-methoxyindan-2-yloxy) phenyl] propionic acid and isomers;

3- [3-amino-5- (1-ethyl-1 H-indazol-5-yl) -4- (5-methoxyindan-2-yloxy) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-dimethoxyindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl] propionic acid;

3- [3-amino-4- (4-benzyloxyindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (4-benzyloxyindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl] propionic acid and isomers;

3- [3-amino-4- (5,6-dibenzyloxyindan-2-yloxy) -5- (1-ethyl-1H-indazol-5-yl) phenyl] propionic acid.

Although an Example and a test example are given to the following and this invention is demonstrated in detail below, this invention is not limited to these.

(Example 1)

Preparation Example 1 of Crystal of 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate (Compound 2)

3- [3-bromo-4- (indan-2-yloxy) -5-nitrophenyl] methyl propionate (14.00 g, prepared according to the method of WO 03/70686), 1-methyl- 1H-indazol-5-boric acid (7.62 g, prepared according to the method of WO 03/70686), palladium acetate (75 mg, manufactured by Wako Pure Chemical Industries, Ltd.), triphenylphosphine (0.17) g, THF (40 mL) was added to and stirred, and then tripotassium phosphate (16.97 g, manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in water (27 mL). The solution was added to nitrogen-substitute the system. Subsequently, the mixture was stirred at 60 ° C. for 4 hours to react. After confirming that the reaction was completed, liquid-separated to obtain an upper layer. After cooling the upper layer to room temperature, ethyl acetate (40 ml) and activated carbon (2.8 g, manufactured by Japan Enviro Chemicals.ltd) were added, and the mixture was stirred at room temperature for 1 hour. The suspension was filtered to obtain a filtrate, and the residue on the filter was washed with ethyl acetate (20 mL) to obtain a washing solution, and the filtrate and washing solution were concentrated under reduced pressure together to obtain a concentrate (44 g). Subsequently, acetone (140 ml) was added to the concentrate, followed by stirring. Then, water (140 ml) was added at room temperature over 1 hour with stirring, and further stirred at room temperature for 1 hour. Subsequently, this mixed solution was filtered and the solid on the filter was further washed with water (70 ml) to obtain a wet solid. The wet solid was dried under reduced pressure at 50 ° C to obtain crystals of the title compound (15.7 g).

(Example 1-A, B)

Preparation Example 2 of Crystal of Compound 2

Regarding the operation following the acquisition of the concentrate of Example 1, crystals of the compound can be obtained by using toluene instead of acetone and heptane instead of water.

In addition, crystals of Compound 2 can be obtained by using tetrahydrofuran instead of acetone of Example 1 and heptane instead of water.

(Example 2)

Preparation Example 1 of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate (Compound 3)

THF (138 mL), stabilized nickel (4.42 g, manufactured by NIKKI CHEMICAL CO., LTD), water (4 mL) were added to Compound 2 (13.0 g) prepared according to Example 1, followed by stirring. It substituted and made it react by stirring at 50 degreeC for 7 hours in hydrogen atmosphere. After confirming that the reaction was completed, the reaction solution was nitrogen-substituted and filtered to obtain a filtrate, and the residue on the filter was further washed with THF (34 mL) to obtain a wash solution. Activated carbon (2.6 g, manufactured by Japan Enviro Chemicals ltd) was added to the solution obtained by combining the filtrate and the washing solution, and the mixture was stirred at room temperature for 1 hour. The suspension was filtered to obtain a filtrate, and the residue on the filter was further washed with THF (34 mL) to obtain a wash solution. Water (207 mL) was added to the solution obtained by combining the filtrate and washing liquid obtained at room temperature over 1 hour, and further stirred under ice cooling for 1 hour. Subsequently, this mixed solution was filtered, and the solid on the filter was further washed with water (68 ml) to obtain a wet solid. The wet solid was dried under reduced pressure at 50 ° C to obtain crystals of the title compound (10.3 g).

(Example 2-A, B)

Preparation Example 2 of Compound 3

The crystal of Compound 3 can be obtained by using heptane instead of water added to the mixed solution of the filtrate and the washing solution in Example 2.

Moreover, the crystal of this compound 3 can be obtained by using isopropanol as a solvent.

(Example 3)

Preparation Example 1 of Form A Crystals of Compound 1

Methanol (45 mL) was added to the compound 3 (10.0 g) obtained in Example 2, followed by stirring, followed by addition of 2N aqueous sodium hydroxide solution (17.0 mL) and alkali hydrolysis at 60 ° C under stirring for 3 hours. After the reaction, the reaction solution was cooled to 35 ° C, a 2N aqueous hydrochloric acid solution (17.0 ml) was added over 2 hours, and further stirred at 35 ° C for 16 hours. Subsequently, this mixed solution was filtered, and the filter solid was further washed with a mixed solution of water (27 mL) and methanol (13 mL) to obtain a wet solid. 9.2 g of crystals were obtained by drying the wet solid at 50C under reduced pressure.

(Example 4)

Preparation Example 1 of Form B Crystal of Compound 1

Acetone (17 ml) was added to Form A crystals (1.0 g) of Compound 1 prepared according to Example 3, and the mixture was dissolved in a 60 DEG C water bath. The solution was then stirred overnight at room temperature. The resulting precipitate was filtered to give a solid on the filter. Then, 0.55 g of crystals were obtained by drying under reduced pressure at 50 ° C.

(Example 5)

Preparation Example 2 of Form B Crystals of Compound 1

Dichloromethane (31 ml) was added to Form A crystals (1.0 g) of Compound 1 prepared according to Example 3, and the resultant was dissolved by heating in a water bath at 40 ° C. The solution was then stirred overnight at room temperature. The resulting precipitate was filtered to give a solid on the filter. Subsequently, 0.81 g of crystals were obtained by drying under reduced pressure at 50 ° C.

The crystal | crystallization showed the spectrum substantially the same as FIG. 7 by the differential scanning calorimetry of the test example 4 mentioned later, and it was confirmed that it is a form B crystal of this compound 1.

(Example 6)

Preparation Example 3 of Form B Crystals of Compound 1

Methanol (45 mL) was added to the Form A crystals (10.0 g) of Compound 1 prepared according to Example 3, followed by stirring, followed by addition of an aqueous sodium hydroxide solution (17.0 mL), followed by stirring at 60 ° C for 1 hour. The mixture was cooled to 35 ° C., and a 2-quad hydrochloric acid aqueous solution (7.0 ml) was added for 30 minutes to confirm that the pH of the mixed solution reached 7 to 9, followed by the prompt preparation of Form B crystals of Compound 1 prepared according to Example 4. Seed crystals (0.1 g) were added and stirred for 10 minutes. Subsequently, 2N hydrochloric acid aqueous solution (10.0 ml) was added to this liquid mixture over 1 hour, and it stirred at 35 degreeC for 2 hours further. Subsequently, this mixed solution was filtered, and the filter solid was further washed with a mixed solution of water (27 mL) and methanol (13 mL) to obtain a wet solid. 9.7 g of white crystals were obtained by drying this wet solid under reduced pressure at 50 degreeC.

The crystal | crystallization showed the spectrum substantially the same as FIG. 6 by the powder X-ray diffraction measurement of the test example 3 mentioned later, and it was confirmed that it is a form B crystal of the compound 1. Moreover, the crystal showed the spectrum substantially the same as FIG. 7 by the differential scanning calorimetry of the test example 4 mentioned later, and it was confirmed that it is a B type crystal.

(Example 7)

Preparation Example 4 of Form B Crystals of Compound 1

Methanol (360.0 mL) was added to the compound 3 (80.0 g) obtained by the method according to Example 2, followed by stirring, followed by addition of water (36.2 mL) and a bisodium hydroxide aqueous solution (99.7 mL). Alkali hydrolysis under time stirring. After the reaction, an insoluble matter such as dust in the reaction solution was separated by filtration, and water (180.2 ml) was added thereto, followed by adjusting to 35 ° C. After adding 2 N hydrochloric acid aqueous solution (10.7 ml) to the mixed solution over 8 minutes to confirm that the pH of the mixed solution was 7.9, the seed crystals of Form B crystals of Compound 1 prepared rapidly according to Example 4 (0.08 g) Was added and stirred for 4 minutes. Subsequently, 2N hydrochloric acid aqueous solution (89.0 ml) was added to this liquid mixture over 111 minutes, and it stirred at 35 degreeC for 14.3 hours further. Subsequently, this mixed solution was filtered, and the filter solid was further washed with a mixed solution of water (213.4 mL) and methanol (106.7 mL) to obtain a wet solid. Water (213.4 mL) and methanol (106.7 mL) were added to this wet solid, and it was made into a liquid mixture again, and it stirred at 18-20 degreeC for 37 minutes. Subsequently, this mixed solution was filtered, and the filter solid was further washed with a mixed solution of water (21.3 mL) and methanol (10.7 mL) to obtain a wet solid. 76.28 g of white crystals were obtained by drying this wet solid under reduced pressure at 50 degreeC.

The crystal | crystallization showed the spectrum substantially the same as FIG. 7 by the differential scanning calorimetry of the test example 4 mentioned later, and it was confirmed that it is a form B crystal of this compound 1.

(Example 8)

Preparation Example 1 of Mixed Crystal of Compound 1

A mixture of 90% of Form A crystals and 10% of Form B crystals was mixed with 0.9 g of Form A crystals of Compound 1 prepared in Example 3 and 0.1 g of Form B crystals prepared in Example 4 using a mortar and pestle. Got.

(Example 9)

Preparation Example 2 of Mixed Crystal of Compound 1

0.1 g of Form A crystals of Compound 1 prepared according to Example 3 and 0.9 g of Form B crystals prepared according to Example 4 were mixed using mortar and pestle to prepare 10% of Form A crystals and 90% of Form B crystals. A mixture was obtained.

(Example 10)

Preparation Example 2 of Form A Crystals of Compound 1

Compound 3 (3.92 kg), obtained by the method according to Example 2, was added to Reactor A (proportion: BD-1, 30 L lift-type reactor, manufactured by ASAHI TECHNO GLASS CO., LTD), and methanol (14.08) was added thereto. Kg) was added and stirred. After adding 2N aqueous sodium hydroxide solution (6.76 kg), it heated at 60.6 degreeC over 27 minutes. After stirring at about 60 degreeC for 4 hours and 9 minutes, it cooled to 35 degreeC over 19 minutes, The reaction liquid was filtered through the membrane filter, and the reaction liquid 1 was prepared. In addition, Compound 3 (3.92 kg) obtained in accordance with Example 2 was added to Reactor A, and methanol (14.25 kg) was added thereto and stirred. After adding 2N sodium hydroxide aqueous solution (6.70 kg), it heated at 60.0 degreeC over 30 minutes. After stirring for 4 hours and 30 minutes at about 60 ° C., the mixture was cooled to 34.6 ° C. over 17 minutes, and the reaction solution was filtered through a membrane filter to react with reaction device B (model number: BD-2, 100 L lift-type reaction device, ASAHI TECHNO GLASS). CO., LTD.) Was combined with the reaction solution 1 to prepare a reaction solution 2. The reaction liquid 2 was kept at 30-35 degreeC, the 2-normal hydrochloric acid aqueous solution (13.30 kg) was dripped over 5 hours 48 minutes, stirring, and crystal | crystallization was deposited and the crystallization liquid was prepared. After further stirring for 10 hours and 5 minutes while maintaining the crystallized solution at about 35 ° C, the resultant was poured into a filter (prototype: F-9, a φ600 mm nutche filter, manufactured by ASAHI ENGINEERING CO., LTD.), Filtered by suction, and wetted. A decision was obtained. The wet crystal on the filter was added with a mixed solution of water (20.00 kg) and methanol (7.88 kg) to suck the wet crystal. Suction was continued and dewatered sufficiently, and the wet crystal (15.571 kg) of the Form A crystal of the compound 1 was obtained. At this time, the time required for obtaining the wet crystal from the crystallized solution by filtration was 1 hour 5 minutes, the time required for washing in the mixed liquid of the water and methanol of the wet crystal on the filter was 1 hour 44 minutes, and the time required for dehydration. Was 50 minutes. The wet crystals are sprinkled on a tray and placed in a drier (formerly BM-6, shelf-type vacuum drier, VAC-300PR, manufactured by ESPEC CORP.), And dried under reduced pressure at 50 ° C. for 3 days (over 65 hours 52 minutes). A crystal (1.402 kg) of 1 was obtained.

The crystal | crystallization showed the spectrum substantially the same as FIG. 3 by the powder X-ray diffraction measurement of the test example 3 mentioned later, and it was confirmed that it is a form A crystal of the compound 1. Moreover, the crystal | crystallization showed the spectrum substantially the same as FIG. 4 by the differential scanning calorimetry analysis of the test example 4 mentioned later, and it was confirmed that it is a form A crystal of the compound 1.

(Example 11)

Preparation Example 5 of Form B Crystals of Compound 1

Compound 3 (3.90 kg), obtained by the method according to Example 2, was added to Reactor A (proportion: BD-1, 30 L lift-type reactor, manufactured by ASAHI TECHNO GLASS CO., LTD), and methanol (13.75) was added thereto. Kg) was added and stirred. After adding 2N aqueous sodium hydroxide solution (5.20 kg) and water (1.75 kg), it heated at 60 degreeC over 42 minutes. After stirring at about 60 degreeC for 2 hours and 29 minutes, it cooled to 35.0 degreeC over 13 minutes, The reaction liquid was filtered through the membrane filter, and the reaction liquid 1 was prepared. In addition, Compound 3 (3.90 kg) obtained in accordance with Example 2 was added to Reactor A, and methanol (13.97 kg) was added thereto and stirred. After adding 2N sodium hydroxide aqueous solution (5.20 kg) and water (1.75 kg), it heated at 60 degreeC over 40 minutes. After stirring for 2 hours and 34 minutes at about 60 ° C., the mixture was cooled to 35.0 ° C. over 19 minutes, and the reaction solution was filtered through a membrane filter to react with reaction device B (model number: BD-2, 100 L lift-type reaction device, ASAHI TECHNO GLASS). CO., LTD.) Was combined with the reaction solution 1 to prepare a reaction solution 2. After adding water (17.36 kg) to the reaction solution 2, the solution was added dropwise over 38 minutes while maintaining the solution at 30 to 35 DEG C while stirring, and then dropwise added when the pH reached 7.90. Stopped. Subsequently, after adding the Form B crystal (7.795 g) of the compound 1, 2N hydrochloric acid aqueous solution (9.08 kg) was dripped over 3 hours and 50 minutes, and the crystal | crystallization was precipitated and the crystallization liquid was prepared. The crystallized solution was kept at about 35 ° C., stirred for 8 hours and 42 minutes, and then charged into a filter (product number: F-9, φ600 mm nutche filter, manufactured by ASAHI ENGINEERING CO., LTD.) In the same manner as in Example 10. Filtration was carried out by suction to obtain a wet crystal. To the wet crystal obtained on this filter, a mixed liquid of water (20.78 kg) and methanol (8.10 kg) was added and aspirated to wash the wet crystal. Suction was continued and dewatered sufficiently, and the wet crystal | crystallization of the form B crystal of this compound 1 was acquired. At this time, the time required for obtaining the wet crystal from the crystallized solution by filtration was 8 minutes, the time required for washing the wet crystal on the filter in the mixed liquid of water and methanol was 10 minutes, and the time required for dehydration was 37 minutes. In order to further increase the purity of the wet crystals, the mixture was poured into a mixture of water (21.00 kg) and methanol (8.18 kg) to form a suspension, followed by stirring for 34 minutes to wash the crystals. Mm millet filter, manufactured by ASAHI ENGINEERING CO., LTD. Subsequently, a mixture of water (2.10 kg) and methanol (0.80 kg) was added to a filter, filtered by suction to obtain a wet crystal, continued suction, and sufficiently dehydrated to obtain a wet crystal of Form B crystal of Compound 1 ( 12.211 kg) was obtained. At this time, the time required for obtaining the wet crystal from the suspension by filtration was 4 minutes and the time required for dehydration was 16 minutes. The wet crystals were sprayed on a tray and placed in a dryer (proportion: BM-6, shelf-type vacuum dryer, VAC-300PR, manufactured by ESPEC CORP.) And dried under reduced pressure at 50 ° C. for 3 days (over 71 hours and 3 minutes). Form B crystals (1.412 kg) were obtained.

The crystal | crystallization showed the spectrum substantially the same as FIG. 6 by the powder X-ray diffraction measurement of the test example 3 mentioned later, and it was confirmed that it is a form B crystal of the compound 1. Moreover, the crystal | crystallization showed the spectrum substantially the same as FIG. 7 by the differential scanning calorimetry of the test example 4 mentioned later, and it was confirmed that it is a form B crystal of this compound 1.

(Test Example 1)

Measurement of filtration rate 1

To the Form A crystal (5.0 g) of Compound 1 prepared according to Example 3, a mixed solution of methanol and water (mixture ratio 1: 2) (50 ml) was added and stirred at 25 ° C for 30 minutes, followed by Kiriyama lot (40 mm inside diameter). It filtered using the filter paper No. 3 for Kiriyama lot) and a suction machine. At this time, 2 minutes 37 seconds to obtain 10 ml of the filtrate, 7 minutes 45 seconds to obtain 20 ml of the filtrate, 15 minutes and 14 seconds to obtain 30 ml of the filtrate, and finally 25 minutes 24 seconds 40 ml of filtrate was obtained. In addition, 4.9 g of crystals were obtained by drying the wet lot product under reduced pressure at 50 ° C.

In addition, a methanol: water (1: 2) mixed solution (50 ml) was added to Form B crystal (5.0 g) of Compound 1 prepared according to Example 4, followed by stirring at 25 ° C for 30 minutes, followed by Kiriyama lot (inner diameter 40). It filtered using mm, the filter paper No. 3 for Kiriyama lot, and an inhaler. It took 8 seconds to obtain 10 ml of the filtrate, 17 seconds to obtain 20 ml of the filtrate, and 28 seconds to obtain 30 ml of the filtrate, and finally 2 minutes to obtain 42 ml of the filtrate. Further, 4.7 g of crystals were obtained by drying the wet lot product under reduced pressure at 50 ° C.

As in the above example, the time required for obtaining the Form B crystals may be less than one-tenth as compared with the time required for obtaining almost the same amount of Form A crystals, and thus excellent filterability of the Form B crystals of the present invention. Could confirm.

(Test Example 1-2)

Measurement of filtration rate 2

The filterability of the Form A crystals of Compound 1 in Example 10 and the filterability of the Form B crystals of Compound 1 in Example 11 were compared. Regarding each, (1) the time until the crystallized solution is introduced into the filter and aspirated to separate the wet crystal and the mother liquid, (2) Then, the mixed liquid of water and methanol is introduced into the filter containing the wet crystal and aspirated by As a result of comparing the time required for washing the crystals, (3) the time from the last suction to the water content of the wet crystal after washing, and the three steps of, the type A crystals were (1) 1 hour 5 Minutes, (2) 1 hour 44 minutes, (3) 50 minutes, whereas in the type B crystal, (1) 8 minutes, (2) 10 minutes, (3) 37 minutes, Excellent filterability could be confirmed.

(Test Example 1-3)

Measurement of moisture content after filtration

When the water content of each crystal obtained in Examples 10 and 11 was calculated from the weight of the wet crystal and the weight of the crystal after drying, the crystal of Form A was 52.5%, the Form B crystal was 39.3%, and Form B of the present invention. It was confirmed that the crystal was excellent also in dryness. The results are shown in Table 1. In Example 10 and Example 11, both were dried for 3 days, but it can be easily estimated that the time and energy actually required for drying are lower in type B crystals having a lower moisture content.

TABLE 1

Table 1: Moisture Content Measurement Results

decision Weight of wet crystal (kg) Weight of Crystals After Drying (kg) Moisture content (%) Form A crystal (Example 10) 15.571 7.402 52.5 Form B crystal (Example 11) 12.211 7.412 39.3

(Test Example 2)

Solubility test

10 mg of Form A crystals of Compound 1 prepared according to Example 3 and Form B crystals of Compound 1 prepared according to Example 4 were respectively weighed in a 10 ml centrifuge tube, and the first solution of the Japanese Pharmacopoeia Disintegration Test Solution (pH1.2) ) 3 ml each) was added and shaken at 37 ° C for 24 hours. After shaking, the solution was filtered, 1 ml of the filtrate was accurately weighed, and 1 ml of acetonitrile was accurately added to obtain a sample solution.

About the sample solution, the solubility was calculated | required by measuring the density | concentration of the sample solution with the standard solution whose density | concentration is known on the following HPLC conditions.

The solubility was obtained in the same manner as for the second liquid (pH6.8) of the Japanese Pharmacy Disintegration Test Solution.

The results are shown in Table 3.

TABLE 2

Condition

Injection volume: 10µl

Detector: ultraviolet absorbance photometer (measured wavelength: 235 nm)

Mobile phase: 50 mmol / L sodium dihydrogen phosphate / acetonitrile mixture (55:45)

Column: YMC-Pack Pro C18 inner diameter 4.6㎜, length 15㎝ (manufactured by YMC)

Column temperature: 40 ℃

Flow rate: 1.0 ml / min

TABLE 3

Table 3: Solubility Test Results

decision Solubility (mg / mL) in the first solution (pH1.2) Solubility (mg / mL) in Japan Pharmaceutical Defense Collapse Test Solution 2 (pH6.8) A type crystal 0.03 0.06 Type B crystal 0.01 0.02

(Test Example 2)

As shown in Table 2, the solubility of Form A crystals in the first solution (pH1.2) and the second solution (pH6.8) of the Japanese Pharmacopoeia Disinfection Test Solution was three times that of Form B crystals. High solubility of Form A crystals was confirmed.

(Test Example 3)

Powder X-ray Diffraction

Powder X-ray diffraction was performed on the crystal obtained in each example of the present specification.

TABLE 4

Measuring conditions

X-ray diffractometer: Shimadzu Corporation. XRD-6000 of manufacture

X-ray source: CuKα (40kV30mA)

Injection mode: continuous

Scan Speed: 2 ° / min

Scan step: 0.02 °

Scan drive shaft: θ-2θ

Injection range: 5 ° -40 °

Scattering Slit: 1 °

Light receiving slit: 0.30 mm

The result of the measurement was as follows.

The spectrum shown in FIG. 1 was obtained when the crystal of this compound 2 obtained in Example 1 was measured. In the powder X-ray diffraction spectrum of the crystal of Compound 2, characteristic peaks having 2θ of 7.6 °, 15.3 °, 18.0 °, 21.3 °, and 26.9 ° were identified. Moreover, a peak is confirmed also in any one or all of 16.3 degrees, 20.4 degrees, 23.0 degrees, or 30.5 degrees, and any one of these can also be grasped | ascertained as a characteristic peak. In addition, the peak is confirmed also in any one or all of 11.5 degrees, 19.1 degrees, 25.1 degrees, or 25.8 degrees, and any one of these may be regarded as a characteristic peak at least. Although this crystal was determined to be a crystal even by visual observation, it was confirmed that the crystal was reliably also by the analysis data.

Moreover, the spectrum shown in FIG. 2 was obtained when the crystal of this compound 3 obtained in accordance with Example 2 was measured. In the powder X-ray diffraction spectrum of the crystal of the compound 3, peaks characteristic of 2θ at 8.6 °, 12.7 °, 17.2 °, 17.6 °, 18.9 °, and 21.0 ° were confirmed. Moreover, a peak is confirmed also in any one or all of 14.7 degrees, 18.4 degrees, 19.4 degrees, or 22.1 degrees, and any one of these can also be grasped | ascertained as a characteristic peak. Moreover, a peak is confirmed also in any one or all of 11.9 degrees, 14.2 degrees, 23.0 degrees, 24.7 degrees, 26.1 degrees, 26.8 degrees, or 32.6 degrees, and any of these can be regarded as a characteristic peak at least. Although this crystal was determined to be a crystal even by visual observation, it was confirmed that the crystal was reliably also from the analytical data.

Moreover, the spectrum shown in FIG. 3 was obtained when the A-type crystal | crystallization of this compound 1 obtained in accordance with Example 3 was measured. In the powder X-ray diffraction spectrum of Form A crystal of Compound 1, peaks characteristic of 2θ at 6.9 °, 14.4 °, 16.4 °, 18.2 °, 25.0 °, and 27.5 ° were confirmed. Moreover, a peak is confirmed also in any or all of 20.0 degrees, 20.7 degrees, 22.9 degrees, or 25.4 degrees, and any one of these can also be grasped | ascertained as a characteristic peak. In addition, the peak is confirmed also in any one or all of 10.2 degrees, 12.7 degrees, 15.0 degrees, or 23.8 degrees, and any one of these may be regarded as a characteristic peak at least.

Moreover, the spectrum shown in FIG. 6 was obtained when the B type crystal | crystallization of this compound 1 obtained in Example 6 was measured. In the powder X-ray diffraction spectrum of Form B crystal of Compound 1, peaks characteristic of 2θ at 14.4 °, 15.9 °, 17.3 °, 22.2 °, and 22.9 ° were confirmed. Moreover, a peak is confirmed also in any or all of 8.6 degrees, 9.8 degrees, 21.2 degrees, 23.6 degrees, or 28.4 degrees, and any one of these can also be grasped | ascertained as a characteristic peak. In addition, peaks are identified at any one or all of 12.6 °, 18.0 °, 18.3 °, 18.8 °, 19.2 °, 19.8 °, 20.4 °, 25.3 °, 26.6 ° or 31.8 °, any one of which is at least characteristic It can also be seen as a peak.

(Test Example 3-2)

How to Measure Crystal Purity

In the calculation of the mixing ratio in the case where another crystalline form of Compound 1 is mixed, measurement under the following conditions is exemplified using a parallel beam method optical system using a rotating sample stage of powder X-ray diffraction spectrum measurement. When the A-type crystal is incorporated into the B crystal, for example, pure A-type crystal is used as the standard as a crystal, and from the peak characteristic for the A-type crystal, a suitable peak (for example, as a suitable peak) 6.9 ± 0.2 ° peak), and compare the peak intensity of the standard with the peak intensity of the sample to be measured, i.e. the peak intensity of the sample to be measured divided by the peak intensity of the standard. As a result, the mixing ratio of the A-type crystal in the sample can be calculated.

TABLE 5

Measuring conditions

X-ray diffractometer: RINT2200Ultima + / PC manufactured by Rigaku Corporation

Measuring method: parallel beam method, using a rotating sample table

X-ray source: CuKα (40kV50mA)

Injection mode: continuous

Scan Speed: 2 ° / min

Scan step: 0.02 °

Scan drive shaft: θ-2θ

Injection range: 3 ° -40 °

Scattering Slit: Open

Receiver Slit: Open

Sample table rotation speed: 120rpm

(Test Example 4)

Differential Scanning Calorimetry

1 to 3 mg of the crystals obtained in Examples 3 and 4 of the present specification were placed in an open aluminum pan and heated at a rate of 10 ° C. to 50 ° C. under a dry nitrogen atmosphere using a PYRIS Diamond DSC differential scanning calorimetry device manufactured by PerkinElmer. It measured at ° C / min. Or using the DSC3200 DSC differential scanning calorimetry made by Bruker AXS, it measured at 50 degreeC-220 degreeC at the temperature increase rate of 10 degree-C / min.

The result is as follows.

The chart shown in FIG. 4 was obtained when the A-form crystal of Compound 1 obtained in Example 3 was measured. In the differential scanning calorimetry of Form A crystals of Compound 1, an endothermic peak was found at about 182 ° C. Moreover, the peak which suggests a hydrate or solvate was not specifically confirmed.

Moreover, the chart shown in FIG. 7 was obtained when the B type crystal | crystallization of this compound 1 obtained in accordance with Example 4 was measured. In the differential scanning calorimetry of Form B crystal of Compound 1, an endothermic peak was found at about 203 ° C. Moreover, the peak which suggests a hydrate or solvate was not specifically confirmed.

In addition, the chart of the crystal | crystallization prepared in Example 10 is also substantially the same as FIG. 4, and it turns out that it is the same A-type crystal. Moreover, the chart of each crystal prepared in Examples 5-7 and 11 is also substantially the same as FIG. 7, and it was suggested that it is the same B type crystal.

In the present invention, even if the compound is a hydrate or a solvate, it is not particularly problematic, but it is more preferable that it is an anhydride or a solvent-free solution.

(Test Example 5)

Infrared Absorption Spectrum Analysis

About the crystal | crystallization obtained according to Examples 3 and 6 of this specification, it measured by the potassium bromide purification method.

The result is as follows.

The spectrum shown in FIG. 5 was obtained when the Form A crystal of Compound 1 obtained in Example 3 was measured. As a result, in the infrared absorption spectrum of Form A crystal of Compound 1, remarkable infrared absorption bands were observed at wave numbers 3361, 2938, 1712, 1204, 1011, and 746 cm ^-1 . In addition, infrared absorption bands are also confirmed in any one or all of 3443, 3349, 1620, 1515, 1480, or 1278 cm <^-1> , and any of these may be regarded as a characteristic peak at least. In addition, infrared absorption bands are also identified in any one or all of 3473, 1585, 1432, 1343, 1159, 781, or 615 cm ^-1 , and any of these can be regarded as at least characteristic peaks.

Moreover, the spectrum shown in FIG. 8 was obtained when the B type crystal | crystallization of this compound 1 obtained in accordance with Example 6 was measured. In the infrared absorption spectrum of Form B crystals, remarkable infrared absorption bands were observed at wave numbers 2939, 1720, 1224, 1016 and 751 cm ^-1 . In addition, an infrared absorption band is also confirmed in any one or all of 3407, 3358, 1513, 1476, or 852 cm <^-1> , and any one of these may be regarded as a characteristic peak at least. In addition, infrared absorption bands are also identified in any one or all of 3447, 3325, 1615, 1339, 1157, 945, 783, and 617 cm ^-1 , and any of these can be regarded as at least characteristic peaks.

(Test Example 6)

Quantitative Measurement of Crystals

0.4 A, 0.8, 1.2, 1.6, 2.0, 2.4, 2.8 and 3.2 mg of Form A crystalline standard of Compound 1 were placed in an open aluminum pan and dried under a dry nitrogen atmosphere using a PYRIS Diamond DSC differential scanning calorimetry device manufactured by PerkinElmer. From 50 degreeC to 220 degreeC, it measured by the temperature increase rate of 50 degree-C / min, the area (mJ) of the endothermic peak of about 185 degreeC was calculated | required, and the analytical curve for the determination of A-type crystal | crystallization was created.

In addition, 0.4, 0.8, 1.2, 1.6, 2.0, 2.4, 2.8, 3.2 mg of Form B crystal standard of Compound 1 was placed in an open aluminum pan, and dried nitrogen was obtained using a PYRIS Diamond DSC differential scanning calorimetry device manufactured by PerkinElmer. Under an atmosphere, the temperature was measured at a temperature increase rate of 50 ° C./min from 50 ° C. to 220 ° C., and the area (mJ) of the endothermic peak in the vicinity of about 205 ° C. was obtained, and a calibration curve for the determination of Form B crystals was prepared.

The calibration curve of the A crystal is shown in FIG.

Moreover, the calibration curve of a B-type crystal | crystallization is shown in FIG.

It was confirmed that both type A crystals and type B crystals can be quantified.

Moreover, as a type A crystal standard, the shape acquired especially by the method of Example 3 of this application was preferable, and it performed using the crystal which shows the characteristic single endothermic peak by differential scanning calorimetry analysis. Moreover, as a B-form crystal standard, the shape acquired especially according to the method of Example 4 of this application is preferable, and it performed using the crystal which shows the characteristic single endothermic peak by differential scanning calorimetry analysis.

(Test Example 7)

Quantification of this compound

The compound was detected and quantified under the following HPLC conditions.

TABLE 6

Condition

Sample concentration: 0.2 mg / ml

(Compounds 1 and 3: dissolved in water / acetonitrile mixture (1: 1)

Compound 2: dissolved in acetonitrile)

Injection volume: 10µl

Detector: ultraviolet absorbance photometer (measured wavelength: 235 nm)

Column: YMC-Pack Pro C18 inner diameter 4.6㎜, length 15㎝ (manufactured by YMC)

Column temperature: 40 ℃

Mobile phase A: 50 mmol / L sodium dihydrogen phosphate

Mobile Phase B: Acetonitrile

Feeding program: Change the mixing ratio of mobile phase A and mobile phase B as shown in Table 7 to control the concentration gradient.

Flow rate: 1.0 ml / min

TABLE 7

Table 7: Remittance Program

Number of minutes since injection Mobile phase A (%) Mobile phase B (%) 0 to 45 65 → 20 35 → 80 45-60 65 35

As a result, peaks were observed in Compound 1 for about 15 minutes, Compound 2 for about 30 minutes, and Compound 3 for about 25 minutes.

A calibration curve was obtained using a known amount of each standard of the compound. The calibration curve was linear.

HPLC confirmed that the quantitative measurement of this compound is possible.

(Test Example 8)

Inhibition of PGE ₂ Production from IL-1β Stimulated MG-63 Cells

In accordance with the method of WO 03/70686, the inhibitory effect of the compound on the production of PGE ₂ by interleukin (IL) -1β, an inflammatory stimulant, was investigated.

As a result, all the compounds obtained by a method described in Examples 1-9 was inhibited more than 50% of the production of PGE ₂ caused by IL-1β by 0.1㎛. In addition, at this concentration, no test compound exhibited cytotoxicity. Therefore, this compound is useful as an inhibitor for inflammatory prostaglandin production.

(Test Example 9)

Prevention and Treatment Effect of Rat Adjuvant Arthritis

Investigation of the inhibitory effect of the compound on leg edema in adjuvant arthritis of rats, one of autoimmune diseases and a conditional model of chronic joint rheumatoid, a chronic inflammatory disease, according to the method of WO 03/70686 did. The test compound was suspended in purified water containing 0.5% methyl cellulose and orally administered to test animals at 0.1 to 50 mg / 0.2 ml / kg.

As a result, all the compounds obtained in Examples 3 and 6 were inhibited compared to the positive control for leg edema in adjuvant arthritis.

Moreover, no death of the test animal was confirmed in this test. Therefore, the compound is useful as a prophylactic and / or therapeutic drug for chronic articular rheumatoid and also autoimmune diseases.

(Test Example 10)

Scanning electron microscopy (SEM) observation

SEM observation was performed about the crystal obtained in Examples 3 and 4 of this specification.

The SEM photograph shown in FIG. 11 was obtained when the A-form crystal of Compound 1 of Example 3 was measured.

As a result of measuring the Form B crystal of this compound 1 of Example 4, the SEM photograph shown in FIG. 12 was obtained.

However, these are shown for reference purposes only, and the properties of any crystal of the present invention are not defined by, and need not be limited to, electron microscope images.

Claims (23)

3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, 3- [4- (indan-2-yloxy ) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate, or 3- [3-amino-4- (indan-2-yloxy) -5- (1 -Methyl-1H-indazol-5-yl) phenyl] crystal of compound of methyl propionate. Crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid. Crystal of 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate. Crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate. 3. The crystal of claim 1, wherein the crystal is 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid Wherein, in the powder X-ray diffraction spectrum, 2θ is a Form A crystal having at least one characteristic peak at at least 6.9 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 °, 25.0 ± 0.2 ° or 27.5 ± 0.2 ° Decision characterized by. The crystal of claim 1, 2 or 5, wherein the crystal is 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl Phenyl] propionic acid, and 2θ in the powder X-ray diffraction spectrum shows characteristic peaks at 6.9 ± 0.2 °, 14.4 ± 0.2 °, 16.4 ± 0.2 °, 18.2 ± 0.2 °, 25.0 ± 0.2 ° and 27.5 ± 0.2 ° A crystal characterized by having a type A crystal. The crystal according to claim 1, 2, 5 or 6, wherein the crystal is 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazole -5-yl) phenyl] propionic acid, characterized in that it is a Form A crystal having an endothermic peak of about 182 ° C in differential scanning calorimetry (raising rate 10 ° C / min). The crystal according to claim 1, 2, 5, 6 or 7, wherein the crystal is 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl- It is composed of 1H-indazol-5-yl) phenyl] propionic acid and characterized in that it is an A-type crystal having an infrared absorption band near the wavenumbers 3361, 2938, 1712, 1204, 1011, and 746 cm ^{-1 in the} infrared absorption spectrum. Decision made. 3. The crystal of claim 1, wherein the crystal is 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid Wherein the 2θ in the powder X-ray diffraction spectrum is a Form B crystal having at least one characteristic peak at at least 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° or 22.9 ± 0.2 ° . The method of claim 1, 2 or 9, wherein the crystal is 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl ) Phenyl] propionic acid, in the powder X-ray diffraction spectrum, 2θ is Form B crystal with peaks characteristic at 14.4 ± 0.2 °, 15.9 ± 0.2 °, 17.3 ± 0.2 °, 22.2 ± 0.2 ° and 22.9 ± 0.2 ° Crystal characterized in that the. The crystal according to claim 1, 2, 9 or 10, wherein the crystal is 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazole -5-yl) phenyl] propionic acid, crystal characterized in that it is a Form B crystal having an endothermic peak of about 203 ℃ in differential scanning calorimetry (raising rate 10 ℃ / min). The crystal according to any one of claims 1, 2, 9, 10 or 11, wherein the crystal is 3- [3-amino-4- (indan-2-yloxy) -5- ( Consisting of 1-methyl-1H-indazol-5-yl) phenyl] propionic acid and having an infrared absorption band in the infrared absorption spectrum near wavenumbers 2939, 1720, 1224, 1016 and 751 cm ^-1 . Crystal characterized in that the. The 3- [3-amino-4- (indan-2-yloxy) -5 (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to any one of claims 1 to 12. Crystals, or Form A crystals or Form B crystals, or 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] propionic acid Either the crystal of methyl or the crystal of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate is effective A pharmaceutical composition comprising as a component and containing a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 13, wherein the pharmaceutically acceptable carrier is a dry substance and the pharmaceutical composition is a dry formulation. The 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to any one of claims 5 to 8. A pharmaceutical composition comprising a Form A crystal having a crystal purity of at least 90% by weight or more as an active ingredient, and a pharmaceutically acceptable carrier. The 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid according to any one of claims 9 to 12. A pharmaceutical composition comprising: Form B crystals having a crystal purity of at least 90 wt% or more as an active ingredient, and containing a pharmaceutically acceptable carrier. By adding acid to a solution under basic conditions of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid, 3 Characterized by producing a crystal consisting of-[3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid to obtain a crystal 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl according to any one of claims 5 to 8 ] Method for producing Form A crystals of propionic acid. The solution of claim 17 wherein the solution under basic conditions of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid is , Alkali hydrolyzate of lower alkyl ester of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid A process for producing Form A crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid. 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid, acetone, dichloromethane, methanol, ethyl acetate, methanol 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-) from a solution dissolved in any one or two or more solvents selected from the group consisting of acetic acid mixture and acetonitrile Crystallization of indazol-5-yl) phenyl] propionic acid, 3- [3-amino-4- (indan-2-yloxy) -5- as described in any one of Claims 9-12 characterized by the above-mentioned. A process for producing Form B crystals of (1-methyl-1H-indazol-5-yl) phenyl] propionic acid. Acid was added to a solution under basic conditions of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid, 3 Form B of the compound, just before crystals consisting of-[3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid are produced Form B crystals of a compound are obtained by adding a crystal as seed crystal, The manufacturing method of the crystal | crystallization in any one of Claims 9-12 characterized by the above-mentioned. The solution of claim 20 wherein the solution under basic conditions of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) -phenyl] propionic acid is , Alkali hydrolyzate of lower alkyl ester of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid A process for producing Form B crystals of 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] propionic acid. 3- [4- (indan-2-yloxy) -3- (1 dissolved in one or two or more solvents selected from the group consisting of toluene, ethyl acetate, tetrahydrofuran, acetone, dimethoxyethane, methanol Any one or two or more solvents selected from the group consisting of heptane, diisopropyl ether, isopropanol, t-butylmethyl ether, and water in a solution of methyl-methyl-1H-indazol-5-yl) -5-nitrophenyl] propionate Of 3- [4- (indan-2-yloxy) -3- (1-methyl-1H-indazol-5-yl) -5-nitrophenyl] methyl propionate characterized by addition of Method of making crystals. 3- [3-amino-4- (indan-2-yloxy) -5- (1-methyl dissolved in one or more solvents selected from the group consisting of toluene, ethyl acetate, tetrahydrofuran, acetone 3- [3], wherein the crystal is added to a solution of methyl -1H-indazol-5-yl) phenyl] propionate by adding one or two or more solvents selected from the group consisting of heptane, isopropanol, methanol and water. A process for the preparation of the crystals of -amino-4- (indan-2-yloxy) -5- (1-methyl-1H-indazol-5-yl) phenyl] methyl propionate.

Images